Roberto Andreatini

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Federal University of Paraná



Behavioural pharmacology of anxiety and mood disorders


Scopus Publications

Scopus Publications

  • Role of prelimbic cortex PKC and PKMζ in fear memory reconsolidation and persistence following reactivation
    Thiago Rodrigues da Silva, Ana Maria Raymundi, Leandro José Bertoglio, Roberto Andreatini, and Cristina A. Stern

    Scientific Reports, eISSN: 20452322, Published: 1 December 2020 Springer Science and Business Media LLC
    The persistence of newly acquired memories is supported by the activity of PKMζ, an atypical isoform of protein kinase C (PKC). Whether the activity of conventional and atypical PKC isoforms contributes to reactivated memories to persist is still unknown. Similarly, whether memory reactivation is a prerequisite for interventions to be able to change memory persistence is scarcely investigated. Based on the above, we examined the role of conventional and atypical PKC isoforms in the prelimbic cortex in reconsolidation and persistence of a reactivated contextual fear memory in male Wistar rats. It is shown that (i) inhibiting the PKC activity with chelerythrine or the PKMζ activity with ZIP impaired the persistence of a reactivated memory for at least 21 days; (ii) ZIP given immediately after memory reactivation affected neither the reconsolidation nor the persistence process. In contrast, when given 1 h later, it impaired the memory persistence; (iii) chelerythrine given immediately after memory reactivation impaired the reconsolidation; (iv) omitting memory reactivation prevented the chelerythrine- and ZIP-induced effects: (v) the ZIP action is independent of the time elapsed between its administration and the initial memory test. The results indicate that prelimbic cortex PKC and PKMζ are involved in memory reconsolidation and persistence.

  • Chamomile tea: Source of a glucuronoxylan with antinociceptive, sedative and anxiolytic-like effects
    Pedro Felipe Pereira Chaves, Palloma de Almeida S. Hocayen, Jorge Luiz Dallazen, Maria Fernanda de Paula Werner, Marcello Iacomini, Roberto Andreatini, and Lucimara M.C. Cordeiro

    International Journal of Biological Macromolecules, ISSN: 01418130, eISSN: 18790003, Volume: 164, Pages: 1675-1682, Published: 1 December 2020 Elsevier BV
    Chamomile is one of the most ancient medicinal herbs known to mankind and among its traditional uses are the calming effects. However, few studies explored its effects on the central nervous system (CNS). In this study we further proceed with structural elucidation of polysaccharides from chamomile tea. A highly substituted 4-O-methyl-glucuronoxylan (fraction SN-50R) was purified and chemically characterized, presenting Xyl:GlcA ratio of 1.7:1, Mw of 500 kDa and total sugar content of 98%. Its bioactivity on pain and on CNS was explored. Animals treated with SN-50R presented antinociceptive effect and a dose-dependent decrease in the number of crossings in the activity chamber and in the open field test, as well as a significant reduction in the number of marbles buried when compared to control. These results suggest that SN-50R presented sedative and anxiolytic-like effects and may be contributing for the calming effects obtained by chamomile tea ingestion.

  • The role of prelimbic and anterior cingulate cortices in fear memory reconsolidation and persistence depends on the memory age
    Thiago Rodrigues da Silva, Jeferson Machado Batista Sohn, Roberto Andreatini, and Cristina Aparecida Stern

    Learning & memory (Cold Spring Harbor, N.Y.), eISSN: 15495485, Pages: 292-300, Published: 1 August 2020 Cold Spring Harbor Laboratory
    Reconsolidation is a time-limited process under which reactivated memory content can be modified. Works focused on studying reconsolidation mainly restrict intervention to the moments immediately after reactivation and to recently acquired memories. However, the brain areas activated during memory retrieval depend on when it was acquired, and it is relatively unknown how different brain sites contribute to reconsolidation and persistence of reactivated recent and remote fear memories. Here, we sought to investigate the participation of prelimbic (PL) and anterior cingulate cortices (ACC) in recent (1 d old) and remote (21 d old) fear memory reconsolidation and persistence. Male Wistar rats were submitted to the contextual fear conditioning protocol. Tamoxifen (TMX), an estrogen receptor modulator known to inhibit protein kinase C activity was used to interfere with these processes. When infused into the PL cortex, but not into the ACC, TMX administration immediately or 6 h after recent fear memory reactivation impaired memory reconsolidation and persistence, respectively. TMX administered immediately after remote memory reactivation impaired memory reconsolidation when infused into the PL cortex and ACC. However, remote memory persistence was only affected when TMX was infused 6 h after memory reactivation into the ACC and no effect was observed when TMX was infused 6 h after memory reactivation into PL cortex. Together, the findings provide further evidence on the participation of PL cortex and ACC in reconsolidation of recent and remote fear memories and suggest that the persistence of a reactivated fear memory becomes independent on the PL cortex with memory age and dependent on the ACC.

  • Ketamine effects on anxiety and fear-related behaviors: Current literature evidence and new findings
    Gabriela P. Silote, Sabrina F.S. de Oliveira, Deidiane E. Ribeiro, Mayara S. Machado, Roberto Andreatini, Sâmia R.L. Joca, and Vanessa Beijamini

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, eISSN: 18784216, Volume: 100, Published: 8 June 2020 Elsevier BV
    Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, presents a rapid and sustained antidepressant effect in clinical and preclinical studies. Regarding ketamine effects on anxiety, there is a widespread discordance among pre-clinical studies. To address this issue, the present study reviewed the literature (electronic database MEDLINE) to summarize the profile of ketamine effects in animal tests of anxiety/fear. We found that ketamine anxiety/fear-related effects may depend on the anxiety paradigm, schedule of ketamine administration and tested species. Moreover, there was no report of ketamine effects in animal tests of fear related to panic disorder (PD). Based on that finding, we evaluated if treatment with ketamine and another NMDA antagonist, MK-801, would induce acute and sustained (24 hours later) anxiolytic and/or panicolytic-like effects in animals exposed to the elevated T-maze (ETM). The ETM evaluates, in the same animal, conflict-evoked and fear behaviors, which are related, respectively, to generalized anxiety disorder and PD. Male Wistar rats were systemically treated with racemic ketamine (10, 30 and 80 mg/kg) or MK-801 (0.05 and 0.1 mg/kg) and tested in the ETM in the same day or 24 hours after their administration. Ketamine did not affect the behavioral tasks performed in the ETM acutely or 24 h later. MK-801 impaired inhibitory avoidance in the ETM only at 45 min post-injection, suggesting a rapid but not sustained anxiolytic-like effect. Altogether our results suggest that ketamine might have mixed effects in anxiety tests while it does not affect panic-related behaviors.

  • Characterization of rat ultrasonic vocalization in the orofacial formalin test: Influence of the social context
    Amanda Ribeiro Barroso, Erika Ivanna Araya, Camila Pasquini de Souza, Roberto Andreatini and Juliana Geremias Chichorro

    European Neuropsychopharmacology, ISSN: 0924977X, eISSN: 18737862, Pages: 1213-1226, Published: 1 November 2019 Elsevier B.V.
    Rats emit ultrasonic vocalizations (USVs) about 22 kHz and 50 kHz sound frequency to communicate the presence of negative or positive emotional states, respectively. The calling behavior may be influenced by several factors, including environmental factors. Likewise, pain behavior can be modulated according to the social context, and also can be transferred to conspecifics through direct observation and/or social interaction. Herein we investigated if acute pain induction was related to changes in emission of aversive and appetitive calls and how different social contexts affected the nociceptive behavior and USVs. Our results demonstrated that orofacial formalin injection in rats induced aversive calls in addition to the nociceptive behavior, and both are reduced by systemic treatment with morphine (2.5 mg/kg). Exposure of formalin-injected rats to cagemates had no effect on the nociceptive behavior or calls emitted by the demonstrator, but the observer showed emotional contagion of pain. In contrast, exposure of formalin-injected rats to non-cagemates decreased the nociceptive behavior of the demonstrator, without affecting the calls emission. The emotional contagion was not detected in non-cagemates or in cagemates separated by a visual barrier. In conclusion, we suggest that familiarity and the visual contact contributes to emotional contagion of pain. USV analysis may represent an additional measure in the evaluation of the emotional aspect of orofacial pain, and for the study of pain modulation.

  • PPAR-γ agonist pioglitazone reduces microglial proliferation and NF-κB activation in the substantia nigra in the 6-hydroxydopamine model of Parkinson's disease
    Meira Maria Forcelini Machado, Taysa Bervian Bassani, Valentín Cóppola-Segovia, Eric Luiz Rossa Moura, Silvio Marques Zanata, Roberto Andreatini and Maria Aparecida Barbato Frazão Vital

    Pharmacological Reports, ISSN: 17341140, Pages: 556-564, Published: August 2019 Elsevier B.V.
    BACKGROUND Peroxisome proliferator-activated receptor γ (PPAR-γ) agonists have received much attention in research because of their neuroprotective and anti-inflammatory effects that reduce cell death and halt the progression of neurodegeneration. Thus, this study observed the pioglitazone effects on the main inflammatory markers after 6-hydroxydopamine (6-OHDA) lesion. METHODS The effects of a 5-day administration of the PPAR-γ agonist pioglitazone (30 mg/kg) in male Wistar rats that received bilateral intranigral infusions of 6-OHDA. After surgery, the rats were evaluated in the open-field test on days 1,7,14, and 21. Immediately after the behavioral tests on day 21, the rats were euthanized, and the substantia nigra was removed to analyze the expression of nuclear factor κB (NF-κB) and IκB by western blot. To immunohistochemical, animals were intracardially perfused, with brain removal that was frozen and sectioned, being selected slices of the SNc region to detect tyrosine hydroxylase (TH) immunoreactivity, microglia activation (Iba-1) and NF-κB translocation in the nucleus. RESULTS Pioglitazone protected rats against hypolocomotion and 6-OHDA-induced dopaminergic neurodegeneration on day 7. Decreases in the microglial activation and the NF-κB expression were observed, and the p65 activation was inhibited. CONCLUSIONS These results suggest that pioglitazone may be a potential adjuvant for the treatment of Parkinson`s disease because of its effects on pathological markers of the progression of neurodegeneration.

  • The nitrergic neurotransmission contributes to the anxiolytic-like effect of Citrus sinensis essential oil in animal models
    Palloma de A.S. Hocayen, Etiele Wendler, Débora D. Vecchia, Luiz K.S. Kanazawa, Ana Carolina Issy, Elaine Del Bel and Roberto Andreatini

    Phytotherapy Research, ISSN: 0951418X, eISSN: 10991573, Pages: 901-909, Published: April 2019 John Wiley and Sons Ltd Southern Gate Chichester, West Sussex PO19 8SQ
    Citrus fragrances have been used in aromatherapy for the treatment of anxiety, and the essential oil of Citrus sinensis (sweet orange) has shown promising results, although its mechanism of action was not known. The objective of this study was to evaluate the involvement of nitric oxide (NO) neurotransmission in the anxiolytic-like effect of C. sinensis essential oil. Swiss male mice were submitted to 15 min of C. sinensis essential oil inhalation (1%, 2.5%, 5%, and 10%) and tested in the marble-burying test, neophobia-induced hypophagia, and light/dark test. Locomotor activity was evaluated in an automated locomotor activity box. The coadministration of C. sinensis essential oil with L-arginine (200 mg/kg, i.p.), an NO precursor, was used for the behavioral evaluation of nitrergic system mediation. Additionally, the NO synthase activity was measured by nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) analysis in the cerebral cortex. C. sinensis essential oil exerted anxiolytic-like effect at dose that did not change locomotor activity. Moreover, L-arginine pretreatment prevented this anxiolytic-like effect on marble-burying test. Finally, C. sinensis essential oil reduced the NADPH-d positive cells. Thus, the nitrergic neurotransmission plays a relevant role in the anxiolytic-like effect C. sinensis essential oil.

  • Mania-like elevated mood in rats: Enhanced 50-kHz ultrasonic vocalizations after sleep deprivation
    Etieli Wendler, Camila Pasquini de Souza, Ana Paula Segantine Dornellas, Luis Eduardo Santos, Sergio T. Ferreira, José Carlos Fernandes Galduróz, Markus Wöhr, Rainer K.W. Schwarting and Roberto Andreatini

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, eISSN: 18784216, Pages: 142-150, Published: 10 January 2019 Elsevier Inc.
    Abstract Mania is characterized by elevated drive and mood but animal models of mania have often neglected elevated mood. Ultrasonic vocalizations (USV) of 50‐kHz emitted by rats are thought to index the subject's positive affective state. Fifty‐kHz USV emission is increased by amphetamine, an effect blocked by lithium administration. Sleep deprivation (SD) is an environmental model of mania and the present study evaluated SD effects on behavioral activity and USV emission, together with the impact of lithium treatment. Adult rats were submitted to 24h or 72h SD, and locomotor activity and USV emission were assessed. To test their sensitivity to a standard antimanic drug, these behavioral parameters were also evaluated after acute administration of lithium carbonate (25, 50 or 100 mg/kg, i.p.). Striatal monoamine content was measured post‐mortem. SD (24h and 72h) led to increased locomotor activity, rearing behavior and 50‐kHz USV emission, together with a change in the call profile characterized by an increase in the percentage of frequency‐modulated 50‐kHz USV, which may indicate the mania‐like consequences of SD. Importantly, all SD effects were reverted by lithium administration. SD also led to a decrease in dopamine content in the ventral striatum, while increasing dopamine turnover. In conclusion, SD increased 50‐kHz USV emission, an effect prevented by acute lithium administration. This suggests 50‐kHz USV as a new marker for mania‐like elevated mood, which shows construct validity (associated with increased dopaminergic tone), face validity (reflecting increased positive affect) and predictive validity (high sensitivity to lithium treatment). Highlights50‐kHz Ultrasonic Vocalizations (USV) are proposed as an index of positive affect.Sleep deprivation increased locomotor activity, rearing and 50‐kHz USV.These effects were blocked by lithium pretreatment.50‐kHz USV can be a marker of elevated mood in animal models of mania.

  • S-ketamine reduces marble burying behaviour: Involvement of ventromedial orbitofrontal cortex and AMPA receptors
    Cristina Luz Tosta, Gabriela Pandini Silote, Maria Paula Fracalossi, Ariandra Guerini Sartim, Roberto Andreatini, Sâmia Regiane Lourenço Joca and Vanessa Beijamini

    Neuropharmacology, ISSN: 00283908, eISSN: 18737064, Volume: 144, Pages: 233-243, Published: January 2019 Elsevier Ltd
    &NA; Previous clinical and pre‐clinical studies suggest the involvement of ventromedial orbitofrontal cortex (vmOFC) and glutamatergic neurotransmission in obsessive‐compulsive disorder (OCD). Ketamine, an NMDA glutamatergic receptor antagonist, has shown a rapid and long‐lasting antidepressant effect, but its anti‐compulsive effect has been scarcely investigated. The antidepressant effect of ketamine involves NMDA receptor blockade, AMPA receptor activation, increased serotonin (5‐HT) release and attenuation of nitric oxide (NO) synthesis. It is not known if these mechanisms are involved in ketamine‐induced anti‐compulsive effect. Therefore, we firstly investigated the effect of S‐ketamine in the marble‐burying test (MBT), a model for screening of drugs with potential to treat OCD. Then, we evaluated whether ketamine effects in the MBT would involve the vmOFC, be dependent on AMPA receptors, facilitation of serotonergic neurotransmission and inhibition of nitrergic pathway. Our results showed that single systemic (10 mg/kg) and intra‐vmOFC (10 nmol/side) administration of S‐ketamine reduces marble burying behaviour (MBB) without affecting spontaneous locomotors activity. Pre‐treatment with NBQX (3 mg/kg; AMPA receptor antagonist) blocked the reduction of MBB induced by S‐ketamine. However, pre‐treatment with p‐CPA (150 mg/kg/day; a 5‐HT synthesis inhibitor), WAY100635 (3 mg/kg; a 5‐HT1A receptor antagonist), or L‐arginine (500 mg/kg; a nitric oxide precursor) did not counteract S‐ketamine effect in the MBT. In contrast, associating sub‐effective doses of L‐NAME (10 mg/kg; NOS inhibitor) and S‐ketamine (3 mg/kg) decreased MBB. In conclusion, the reduction of MBB by S‐ketamine strengthens its possible anti‐compulsive effect. The vmOFC is involved in this S‐ketamine effect, which is dependent on the activation of AMPA receptors. HIGHLIGHTSS‐ketamine into the orbitofrontal cortex reduces marble burying behaviour.Reduction of repetitive behaviour by S‐ketamine depends on AMPA receptor activation.Decrease of repetitive behaviour by S‐ketamine does not involve 5‐HT neurons.NOS inhibition facilitates the reduction of marble burying behaviour by S‐ketamine.

  • Sex-specific effects of Cacna1c haploinsufficiency on object recognition, spatial memory, and reversal learning capabilities in rats
    Moria D. Braun, Theresa M. Kisko, Débora Dalla Vecchia, Roberto Andreatini, Rainer K.W. Schwarting and Markus Wöhr

    Neurobiology of Learning and Memory, ISSN: 10747427, eISSN: 10959564, Volume: 155, Pages: 543-555, Published: November 2018 Academic Press Inc.
    &NA; The CACNA1C gene is strongly implicated in the etiology of multiple major neuropsychiatric disorders, such as bipolar disorder, major depression, and schizophrenia, with cognitive deficits being a common feature. It is unclear, however, by which mechanisms CACNA1C variants advance the risk of developing neuropsychiatric disorders. This study set out to investigate cognitive functioning in a newly developed genetic Cacna1c rat model. Specifically, spatial and reversal learning, as well as object recognition memory were assessed in heterozygous Cacna1c+/− rats and compared to wildtype Cacna1c+/+ littermate controls in both sexes. Our results show that both Cacna1c+/+ and Cacna1c+/− animals were able to learn the rewarded arm configuration of a radial maze over the course of seven days. Both groups also showed reversal learning patterns indicative of intact abilities. In females, genotype differences were evident in the initial spatial learning phase, with Cacna1c+/− females showing hypo‐activity and fewer mixed errors. In males, a difference was found during probe trials for both learning phases, with Cacna1c+/− rats displaying better distinction between previously baited and non‐baited arms; and regarding cognitive flexibility in favor of the Cacna1c+/+ animals. All experimental groups proved to be sensitive to reward magnitude and fully able to distinguish between novel and familiar objects in the novel object recognition task. Taken together, these results indicate that Cacna1c haploinsufficiency has a minor, but positive impact on (spatial) memory functions in rats.

  • Potential antidepressant effect of amantadine: A review of preclinical studies and clinical trials
    Inara F. Raupp-Barcaro, Maria A. Vital, José C. Galduróz and Roberto Andreatini

    Revista Brasileira de Psiquiatria, ISSN: 15164446, Pages: 449-458, Published: October-December 2018 Associacao Brasileira de
    OBJECTIVE Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an antidepressant drug. We conducted a systematic review of preclinical and clinical studies addressing the effects of amantadine in animal models of depression and in patients with depression. METHODS PubMed, Science Direct, and Web of Science were searched up to September 1, 2017 to identify clinical and preclinical studies. The following search terms were used: "amantadine AND depress*"; "amantadine AND mood"; "amantadine AND animal models AND antidepres*"; and "amantadine AND (forced swim, learned helplessness, reserpine, chronic mild stress, anhedonia, sucrose preference)." RESULTS Amantadine had antidepressant-like effects in animal models and appeared to potentiate the antidepressant effects of other antidepressants. These preclinical findings have received some support from the results of small open-label clinical trials, suggesting that amantadine can reduce depressive symptomatology and potentiate the antidepressant effects of monoaminergic drugs. In addition to its glutamatergic and dopaminergic effects, the potential antidepressant-like effects of amantadine have been linked to molecular and cellular actions, such as increased expression of neurotrophic factors (e.g., brain-derived neurotrophic factor), activation of σ1 receptors, decreased corticosterone levels, and decreased inflammatory response to stress. CONCLUSION Amantadine is an interesting candidate as new antidepressant drug for the treatment of depression.

  • Diazepam blocks 50 kHz ultrasonic vocalizations and stereotypies but not the increase in locomotor activity induced in rats by amphetamine
    Gisele de Oliveira Guaita, Debora Dalla Vecchia, Roberto Andreatini, Donita L. Robinson, Rainer K. W. Schwarting and Claudio Da Cunha

    Psychopharmacology, ISSN: 00333158, eISSN: 14322072, Volume: 235, Pages: 1887-1896, Published: 1 July 2018 Springer Verlag
    RationaleWe have recently shown that the benzodiazepine diazepam inhibits dopamine release in the NAc and blocks the increased release of dopamine induced by DL-amphetamine. Rewarding stimuli and many drugs of abuse can induce dopamine release in the nucleus accumbens as well as 50-kHz ultrasonic vocalizations (USVs) in rats.ObjectivesIn the present study, we tested the hypothesis that diazepam can also block the increase in locomotor activity and USVs elicited by amphetamine.MethodsFifty-kilohertz USVs, stereotypy, and locomotor behavior were scored in adult male Wistar rats treated with i.p. injections of saline, 3 mg/kg DL-amphetamine, 2 mg/kg diazepam, 0.2 mg/kg haloperidol, or a combination of these drugs.ResultsIn agreement with previous studies, amphetamine caused significant increases in the number of USV calls, stereotypies, and locomotor activity. The D2 dopamine receptor antagonist haloperidol blocked the effects of amphetamine on USVs, stereotypy, and locomotor activity. Diazepam blocked the effect of amphetamine on USV and stereotypy, but not on horizontal locomotion.ConclusionsThese results suggest that diazepam blocks the rewarding effect of amphetamine. This finding is promising for basic research regarding treatments of substance use disorders and evaluation of the impact of benzodiazepines on motivation.

  • Agomelatine's effect on circadian locomotor rhythm alteration and depressive-like behavior in 6-OHDA lesioned rats
    Leonardo C. Souza, Bruno J. Martynhak, Taysa B. Bassani, Joelle de M. Turnes, Meira M. Machado, Eric Moura, Roberto Andreatini and Maria A.B.F. Vital

    Physiology and Behavior, ISSN: 00319384, eISSN: 1873507X, Volume: 188, Pages: 298-310, Published: 1 May 2018 Elsevier
    Parkinson's disease (PD) patients often suffer from circadian locomotor rhythms impairment and depression, important non-motor symptoms. It is known that toxin-based animal models of PD can reproduce these features. In a 6-hydroxydopamine (6-OHDA) intranigral model, we first investigated the possible disturbances on circadian rhythms of locomotor activity. The rats were divided into 6-OHDA and Sham groups. After a partial dopaminergic lesion, the 6-OHDA group showed slight alterations in different circadian locomotor rhythms parameters. In a second experiment, we hypothesized agomelatine, an melatoninergic antidepressant with potential to resynchronize disturbed rhythms, could prevent neuronal damage and rhythm alterations in the same 6-OHDA model. The animals were divided into four groups: 6-OHDA+vehicle, 6-OHDA+ago, Sham+vehicle and 6-OHDA+ago. However, the treated animals (agomelatine 50 mg/kg for 22 days) showed an impaired rhythm robustness, and agomelatine did not induce significant changes in the other circadian parameters nor neuroprotection. Finally, in a third experiment, we examined the effects of agomelatine in the 6-OHDA model regarding depressive-like behavior, evaluated by sucrose preference test. The animals were also divided into four groups: 6-OHDA+vehicle, 6-OHDA+ago, Sham+vehicle and 6-OHDA+ago. The toxin infused animals showed a decrease in sucrose preference in comparison with the vehicle infused animals, however, agomelatine did not prevent this decrease. Our findings indicate that agomelatine worsened circadian locomotor rhythm and was not able to reverse the depressive-like behavior of rats in the 6-OHDA PD model.

  • Effects of ketamine on vocal impairment, gait changes, and anhedonia induced by bilateral 6-OHDA infusion into the substantia nigra pars compacta in rats: Therapeutic implications for Parkinson's disease
    Débora Dalla Vecchia, Luiz Kae Sales Kanazawa, Etiéli Wendler, Palloma de Almeida Soares Hocayen, Estevan Bruginski, Francinete Ramos Campos, Cristina Aparecida Jark Stern, Maria Aparecida Barbato Frazão Vital, Edmar Miyoshi, Markus Wöhr, Rainer K.W. Schwarting and Roberto Andreatini

    Behavioural Brain Research, ISSN: 01664328, eISSN: 18727549, Volume: 342, Pages: 1-10, Published: 16 April 2018 Elsevier B.V.
    GRAPHICAL ABSTRACT Figure. No caption available. &NA; Parkinson's disease is a chronic neurodegenerative disorder characterized by cardinal motor features, such as bradykinesia, but also vocal deficits (e.g. difficulties to articulate words and to keep the tone of voice) and depression. In the present study, rats with bilateral 6‐hydroxydopamine lesion of the substantia nigra pars compacta were evaluated for changes in the emission of 50‐kHz ultrasonic vocalizations, gait impairment (catwalk test), and depressive‐like behaviour (sucrose preference test). Furthermore, we evaluated the effect of repeated treatment (28 days) with ketamine (5, 10, and 15 mg/kg, ip, once per week) or imipramine (15 mg/kg, ip, daily). The lesion had prominent effects on the production of 50‐kHz ultrasonic vocalizations (reduced call numbers, call durations, total calling time, and increased latency to start calling), led to gait impairment (increased run duration and stand of right forelimb) and induced anhedonia (reduced sucrose preference). Also, significant correlations between gait changes, sucrose preference, and ultrasonic calling were found, yet, except for run duration and sucrose preference, these correlations were low indicating that these associations are weak. Importantly, ketamine and imipramine reversed lesion‐induced anhedonia and improved gait impairments, but neither drug improved ultrasonic calling. In conclusion, the substantia nigra lesion with 6‐hydroxydopamine induced subtle motor and non‐motor manifestations, reflecting key features of the wide clinical spectrum of early Parkinson's disease. Furthermore, the present results suggest a potential efficacy of ketamine on depression and gait alterations in Parkinson's disease.

  • Anti-fatigue activity of an arabinan-rich pectin from acerola (Malpighia emarginata)
    Rafael Roberto Klosterhoff, Luiz K.S. Kanazawa, Ana L.D.M. Furlanetto, Joao V.C. Peixoto, Claudia R. Corso, Eliana R. Adami, Marcello Iacomini, Rosalvo T.H. Fogaça, Alexandra Acco, Silvia M.S.C. Cadena, Roberto Andreatini and Lucimara M.C. Cordeiro

    International Journal of Biological Macromolecules, ISSN: 01418130, eISSN: 18790003, Volume: 109, Pages: 1147-1153, Published: 1 April 2018 Elsevier B.V.
    A fraction composed of an arabinan-rich pectin was extracted from acerola fruit (Malpighia emarginata) and named ACWS. This fraction presented 93% of total carbohydrate, relative molecular weight of 7.5×104g/mol, galacturonic acid, arabinose, galactose, xylose and rhamnose in 52.1:32.4:7.2:4.8:3.5 molar ratio and had its structure confirmed by NMR analysis. The anti-fatigue activity of ACWS was evaluated using the weight load swim test on trained mice. ACWS was orally administered at doses of 50mg/kg, 100mg/kg and 200mg/kg for 28days. Plasma biochemical parameters, respiration of permeabilized skeletal muscle fibers, and GSH levels and lipoperoxidation in the brain (pre-frontal cortex, hippocampus, striatum and hypothalamus) were determined. ACWS could lengthen the swimming time, increase the plasma levels of glucose, triglycerides, lactate, and the GSH levels in the hippocampus at all tested doses. The mitochondrial respiratory capacity of the skeletal muscle was increased at middle and high ACWS doses. This study provides strong evidence that M. emarginata pectic polysaccharide supplementation has anti-fatigue activity, can modify the kinetics of energy substrates (carbohydrate and fat) mobilization and the respiratory capacity of the skeletal muscle, as well the antioxidant status in the hippocampus of ACWS treated animals.

  • Cannabidiol disrupts the consolidation of specific and generalized fear memories via dorsal hippocampus CB1 and CB2 receptors
    Cristina A.J. Stern, Thiago R. da Silva, Ana M. Raymundi, Camila P. de Souza, Vinicius A. Hiroaki-Sato, Luiza Kato, Francisco S. Guimarães, Roberto Andreatini, Reinaldo N. Takahashi and Leandro J. Bertoglio

    Neuropharmacology, ISSN: 00283908, eISSN: 18737064, Volume: 125, Pages: 220-230, Published: October 2017 Elsevier Ltd
    Pharmacological interventions able to modulate a fear memory while it is consolidated could have therapeutic value in tempering those maladaptively overconsolidated. Animal and human studies have shown the intensity of unconditioned stimulus delivered during fear conditioning influences qualitative and quantitative aspects of the memory to be established. By varying the shock intensity used for contextual pairing in rats, here we induced specific and more generalized long-term fear memories to investigate whether, how and where in the brain the cannabidiol (CBD; 3.0-30 mg/kg i.p.) could impair their consolidation and related outcomes. When given immediately after their acquisition, it reduced respectively the conditioned fear expression, and fear generalization, ultrasonic vocalizations at 22-kHz and the relative resistance to extinction. CBD had no effects on short-term fear memory, and its delayed treatment no longer affected the consolidation process. As the dorsal hippocampus (DH) modulates fear memory specificity and generalization, and cannabinoid type-1 (CB1) and type-2 (CB2) receptors contribute to consolidation, we investigated their involvement in CBD effects. Both systemic and intra-DH treatment with the CB1 receptor antagonist/inverse agonist AM251 or the CB2 receptor antagonist/inverse agonist AM630 prevented the disrupting CBD effects on consolidation. Since the CBD effects on the endocannabinoid transmission are probably indirect, we investigated and demonstrated the FAAH inhibitor URB597 induced effects similar to those of CBD when given systemically or intra-DH. Altogether, the present results suggest the CBD disrupts the consolidation of different fear memories via anandamide-mediated activation of DH CB1 and CB2 receptors.

  • Animal Models of Mania: Essential Tools to Better Understand Bipolar Disorder
    Aline S. de Miranda, Roberto Andreatini and Antônio L. Teixeira

    Animal Models for the Study of Human Disease: Second Edition, Pages: 1131-1143, Published: 28 June 2017 Elsevier Inc.
    Mania is the hallmark of bipolar disorder but there are relatively fewer animal models of mania than models of depression. The existence of valid animal models is important to develop new effective drugs and to understand the neurobiology of mania. For example, except lithium, the pharmacological treatment of mania relies on drugs that were developed for other disorders, such as antipsychotics and anticonvulsants. Pharmacological models (e.g., amphetamine and ouabain-induced hyperlocomotion) are the most frequently used models of mania, showing good predictive validity (e.g., sensitive to lithium, anticonvulsants, or antipsychotics) and giving interesting results about neurobiology of mania (e.g., oxidative stress increase and protein kinase C hyperactivity). Furthermore, studies using these models have suggested antimanic-like effects of some promising compounds. However, these models have some drawbacks, such as potential false results due to pharmacokinetics interaction, acute response to treatment that did not correlate with clinical data, and they frequently rely on just one behavioral variable. Other approaches to model mania in rodents are environmentally (e.g., sleep deprivation) or genetically (e.g., knockout DAT mice) based models. These models are promising and apparently they overcome some limitations of pharmacologically based models, but they are less validated and used. Finally, new behavioral readouts have been proposed (hole exploration by mice and high frequency ultrasound vocalizations in rats) which can refine these models and increase their content and face validity.

  • Fish oil prevents rodent anxious states comorbid with diabetes: A putative involvement of nitric oxide modulation
    Isadora Pozzetti Siba, Mariza Bortolanza, Maria Aparecida Barbato Frazão Vital, Roberto Andreatini, Joice Maria da Cunha, Elaine Aparecida Del Bel and Janaína Menezes Zanoveli

    Behavioural Brain Research, ISSN: 01664328, eISSN: 18727549, Volume: 326, Pages: 173-186, Published: 30 May 2017 Elsevier B.V.
    HighlightsDiabetic rats exhibited a pronounced anxiogenic‐like behavior.Fish oil treatment prevented the anxiogenic‐like behavior in diabetic animals.Fish oil treatment prevented the high nNOS expression in brain areas related to anxiety.Treatment with nitric oxide precursor abolished the anxiolytic effect induced by fish oil. Abstract There is an urgent need to understand the pathophysiological mechanisms related to anxiety associated with diabetes, seeking more effective alternative treatments to treat it. For that, the effect of a preventive and prolonged treatment with fish oil (FO), a source of omega‐3 polyunsaturated fatty acid, was tested in streptozotocin‐diabetic (DBT) rats submitted to the anxiety tests. Additionally, an immunohistochemistry for neuronal NO synthase (nNOS) was performed in brain areas related to anxiety, such as lateral amygdala (AMY), hippocampus (HIP) and dorsolateral periaqueductal gray (dlPAG). Lastly, the effect of NO precursor L‐arginine (L‐Arg) or nNOS inhibitor 7‐nitroindazole (7‐NI) was tested in DBT animals treated with vehicle (VEH) or FO. Our data demonstrated that vehicle‐treated DBT animals exhibited a more pronounced anxiogenic‐like response and also presented high nNOS levels in the AMY, HIP and rostral dlPAG, what were both significantly prevented by FO treatment. This treatment was able to prevent the impairment in locomotor activity besides improving the high glycemic levels in DBT rats. Interestingly, while injection of 7‐NI or L‐Arg in VEH‐treated DBT animals induced an anxiogenic‐like and anxiolytic‐like effect, respectively; the previous treatment with both L‐Arg and 7‐NI in FO‐DBT animals abolished the anxiolytic‐like effect induced by FO treatment. Altogether, our data support the hypothesis that a dysregulation in the NO production in brain areas as AMY, HIP and dlPAG may contribute to the mechanisms that link anxiety and diabetes, and the prevention of nNOS brain expression changes induced by a prolonged treatment with FO may be an important mechanism related to its anxiolytic‐like effect.

  • Effects of acute and chronic quercetin administration on methylphenidate-induced hyperlocomotion and oxidative stress
    Luiz K.S. Kanazawa, Débora D. Vecchia, Etiéli M. Wendler, Palloma de A.S. Hocayen, Paulo S. Beirão, Manuela L. de Mélo, Francislaine A. dos Reis Lívero, Claudia Rita Corso, Maria Carolina Stipp, Alexandra Acco and Roberto Andreatini

    Life Sciences, ISSN: 00243205, eISSN: 18790631, Volume: 171, Pages: 1-8, Published: 15 February 2017 Elsevier
    Aims: Increases in protein kinase C (PKC) and oxidative stress have been related to mania. Drugs with antioxidant effects or inhibitory actions on PKC may have antimanic effects. The flavonoid quercetin has antioxidant and PKC‐inhibiting effects that resemble those of lithium, the first‐line treatment for mania in bipolar disorder. We hypothesized that quercetin may have antimanic‐like effects in an animal model. Main methods: In the present study, we investigated the effects of acute and chronic treatment with quercetin (2.5, 5, 10, and 40 mg/kg, i.p.) in male Swiss mice that were subjected to methylphenidate (5 mg/kg, i.p.)‐induced hyperlocomotion, an animal model of mania. Lithium (100 mg/kg, i.p.) and diazepam (5 mg/kg, i.p.) were used as positive and negative controls, respectively. We also evaluated the effects of these treatments on methylphenidate‐induced oxidative stress in the brain by measuring reduced glutathione (GSH) and lipid peroxidation (LPO) levels in the prefrontal cortex, hippocampus, and striatum. Key findings: Acute and chronic (21‐day) treatment with lithium and diazepam reduced methylphenidate‐induced hyperlocomotion. Chronic but not acute treatment with quercetin (10 and 40 mg/kg) blocked methylphenidate‐induced hyperlocomotion. These effects of lithium and quercetin occurred at doses that did not alter spontaneous locomotor activity, whereas diazepam reduced spontaneous locomotor activity. Chronic treatment with lithium and quercetin blocked the methylphenidate‐induced increase in LPO levels in the striatum. Significance: These results suggest that chronic quercetin treatment has antimanic‐like and antioxidant effects, thus encouraging further studies of quercetin as a putative new antimanic drug.

  • Transient anhedonia phenotype and altered circadian timing of behaviour during night-time dim light exposure in Per3-/- mice, but not wildtype mice
    Bruno Jacson Martynhak, Alexandra L. Hogben, Panos Zanos, Polymnia Georgiou, Roberto Andreatini, Ian Kitchen, Simon N. Archer, Malcolm Von Schantz, Alexis Bailey and Daan R. Van Der Veen

    Scientific Reports, eISSN: 20452322, Published: 10 January 2017 Nature Publishing Group
    Industrialisation greatly increased human night-time exposure to artificial light, which in animal models is a known cause of depressive phenotypes. Whilst many of these phenotypes are 'direct' effects of light on affect, an 'indirect' pathway via altered sleep-wake timing has been suggested. We have previously shown that the Period3 gene, which forms part of the biological clock, is associated with altered sleep-wake patterns in response to light. Here, we show that both wild-type and Per3-/- mice showed elevated levels of circulating corticosterone and increased hippocampal Bdnf expression after 3 weeks of exposure to dim light at night, but only mice deficient for the PERIOD3 protein (Per3-/-) exhibited a transient anhedonia-like phenotype, observed as reduced sucrose preference, in weeks 2-3 of dim light at night, whereas WT mice did not. Per3-/- mice also exhibited a significantly smaller delay in behavioural timing than WT mice during weeks 1, 2 and 4 of dim light at night exposure. When treated with imipramine, neither Per3-/- nor WT mice exhibited an anhedonia-like phenotype, and neither genotypes exhibited a delay in behavioural timing in responses to dLAN. While the association between both Per3-/- phenotypes remains unclear, both are alleviated by imipramine treatment during dim night-time light.

  • Myricitrin induces antidepressant-like effects and facilitates adult neurogenesis in mice
    Erika Meyer, Marco Aurélio Mori, Alline Cristina Campos, Roberto Andreatini, Francisco Silveira Guimarães, Humberto Milani and Rúbia Maria Weffort de Oliveira

    Behavioural Brain Research, ISSN: 01664328, eISSN: 18727549, Volume: 316, Pages: 59-65, Published: 1 January 2017 Elsevier B.V.
    HighlightsMyricitrin repeated treatment results in antidepressant‐like effects in mice.Myricitrin increases cell proliferation and the number of newborn neurons in the hippocampal dentate gyrus.Myricitrin facilitates differentiation of progenitor cells in neurons in the hippocampus. ABSTRACT Myricitrin (MYR) is a natural flavonoid that inhibits nitric oxide (NO) transmission and has an atypical antipsychotic‐like profile in animal models. Considering that several NO inhibitors exert antidepressant‐like effects, the present study evaluated the antidepressant‐like effect of MYR (3–30 mg/kg) in the tail suspension test (TST). Because of the putative relationship between adult neurogenesis and antidepressant activity, we also assessed cell proliferation, survival, and differentiation in adult neurogenic niches, including the subgranular zone (SGZ) and subventricular zone (SVZ). Similar to the positive control imipramine (IMI; 10 mg/kg), repeated treatment with 10 mg/kg MIR but not acute treatment reduced immobility time in the TST, indicating an antidepressant‐like effect. No effect on general motor activity was observed. Myricitrin also facilitated cell proliferation in the SGZ of the hippocampal dentate gyrus and SVZ. In the SGZ, MYR increased the number of doublecortin‐ and 5‐bromo‐2′‐deoxyuridine/neuronal nuclei‐positive cells. Our results suggest that MYR facilitates hippocampal neurogenesis, which might contribute to its antidepressant‐like effect and atypical antipsychotic‐like profile.

  • Evaluation of 50-kHz ultrasonic vocalizations in animal models of mania: Ketamine and lisdexamfetamine-induced hyperlocomotion in rats
    Etieli Wendler, Camila Pasquini de Souza, Debora Dalla Vecchia, Luiz Kae Sales Kanazawa, Palloma de Almeida Soares Hocayen, Markus Wöhr, Rainer K.W. Schwarting and Roberto Andreatini

    European Neuropsychopharmacology, ISSN: 0924977X, eISSN: 18737862, Pages: 1900-1908, Published: 1 December 2016 Elsevier B.V.
    Drug-induced hyperlocomotion in rodents is frequently used as a behavioral model for mania. However, the use of locomotor activity as the single parameter in these animal models of mania may pose some limitations for developing new pharmacological treatments. Thus, alternative behavioral markers are required. Fifty-kHz ultrasonic vocalizations (USV), which are thought to represent positive affect, are increased by the administration of the psychostimulant d-amphetamine, an effect that can be prevented by lithium treatment, the gold standard antimanic drug for treating bipolar disorder. The aim of this study was to evaluate 50-kHz USV in two other pharmacological-induced animal models of mania: ketamine (KET)- and lisdexamfetamine (LDX)-induced hyperlocomotion. After systemic injection of LDX (10mg/kg, ip), racemic-ketamine (25mg/kg, ip) or S-ketamine (25mg/kg, ip), locomotor activity and 50-kHz USV emission were evaluated in rats. Furthermore, the effects of an antimanic treatment, namely lithium carbonate (100mg/kg, ip), on LDX-induced 50-kHz USV and hyperlocomotion were tested. Rats treated with racemic KET and S-KET showed increased locomotor activity, but these drug treatments did not significantly affect 50-kHz USV emission rates. On the other hand, LDX administration increased both locomotor activity and 50-kHz USV with both effects being reversed by lithium administration. The present findings suggest that 50-kHz USV can differentiate between drug-induced models of mania, which may represent different types of manic episodes. Thus, measuring 50-kHz USV might serve as an additional valuable behavioral variable to assess mania-like phenotypes in rat models.

  • Evidence for an expanded time-window to mitigate a reactivated fear memory by tamoxifen
    Thiago R. da Silva, Reinaldo N. Takahashi, Leandro J. Bertoglio, Roberto Andreatini and Cristina A.J. Stern

    European Neuropsychopharmacology, ISSN: 0924977X, eISSN: 18737862, Pages: 1601-1609, Published: 1 October 2016 Elsevier B.V.
    The mechanisms underpinning the persistence of emotional memories are inaccurately understood. Advancing the current level of understanding with regards to this aspect is of potential translational value for the treatment of post-traumatic stress disorder (PTSD), which stems from an abnormal aversive memory formation. Tamoxifen (TMX) is a drug used in chemotherapy for breast cancer and associated with poor cognitive performances. The present study investigated whether the systemic administration of TMX (1.0-50mg/kg) during and/or beyond the reconsolidation time-window could attenuate a reactivated contextual fear memory in laboratory animals. When administered 0, 6 or 9h (but not 12h) post-memory retrieval and reactivation, TMX (50mg/kg) reduced the freezing behavior in male rats re-exposed to the paired context on day 7, but not on day 1, suggesting a specific impairing effect on memory persistence. Importantly, this effect lasts up to 21 days, but it is prevented by omitting the memory retrieval or memory reactivation. When female rats in the diestrous or proestrous phase were used, the administration of TMX 6h after retrieving and reactivating the fear memory also impaired its persistence. Altogether, regardless of the gender, the present results indicate that the TMX is able to disrupt the persistence of reactivated fear memories in an expanded time-window, which could shed light on a new promising therapeutic strategy for PTSD.

  • Quercetin reduces manic-like behavior and brain oxidative stress induced by paradoxical sleep deprivation in mice
    Luiz K.S. Kanazawa, Débora D. Vecchia, Etiéli M. Wendler, Palloma de A.S. Hocayen, Francislaine A. dos Reis Lívero, Maria Carolina Stipp, Inara M.R. Barcaro, Alexandra Acco and Roberto Andreatini

    Free Radical Biology and Medicine, ISSN: 08915849, eISSN: 18734596, Pages: 79-86, Published: 1 October 2016 Elsevier
    Quercetin is a known antioxidant and protein kinase C (PKC) inhibitor. Previous studies have shown that mania involves oxidative stress and an increase in PKC activity. We hypothesized that quercetin affects manic symptoms. In the present study, manic-like behavior (hyperlocomotion) and oxidative stress were induced by 24h paradoxical sleep deprivation (PSD) in male Swiss mice. Both 10 and 40mg/kg quercetin prevented PSD-induced hyperlocomotion. Quercetin reversed the PSD-induced decrease in glutathione (GSH) levels in the prefrontal cortex (PFC) and striatum. Quercetin also reversed the PSD-induced increase in lipid peroxidation (LPO) in the PFC, hippocampus, and striatum. Pearson's correlation analysis revealed a negative correlation between locomotor activity and GSH in the PFC in sleep-deprived mice and a positive correlation between locomotor activity and LPO in the PFC and striatum in sleep-deprived mice. These results suggest that quercetin exerts an antimanic-like effect at doses that do not impair spontaneous locomotor activity, and the antioxidant action of quercetin might contribute to its antimanic-like effects.

  • Antimanic-like effects of (R)-(-)-carvone and (S)-(+)-carvone in mice
    Francianne P. Nogoceke, Inara M.R. Barcaro, Damião P. de Sousa and Roberto Andreatini

    Neuroscience Letters, ISSN: 03043940, eISSN: 18727972, Volume: 619, Pages: 43-48, Published: April 21, 2016 Elsevier Ireland Ltd
    Carvone is a monoterpene that is present in spearmint (Mentha spicata) and caraway (Carum carvi) essential oils and has been shown to have anticonvulsant effects, likely through the blockade of voltage-gated sodium channels, and anxiolytic-like effects. Considering that some anticonvulsants that blocked voltage-gated sodium channels (e.g., sodium valproate and carbamazepine) exert clinical antimanic effects, the aim of the present study was to evaluate (R)-(-)-carvone and (S)-(+)-carvone in animal models of mania (i.e., hyperlocomotion induced by methylphenidate and sleep deprivation). Mice that were treated with methylphenidate (5mg/kg) or sleep-deprived for 24h using a multiple-platform protocol exhibited an increase in locomotor activity in an automated activity box. This effect was blocked by pretreatment with acute (R)-(-)-carvone (50-100mg/kg), (S)-(+)-carvone (50-100mg/kg), and lithium (100mg/kg, positive control). These doses did not alter spontaneous locomotor activity in the methylphenidate-induced experiments while (S)-(+)-carvone decreased spontaneous locomotor activity in sleep deprivation experiment, indicating a sedative effect. Chronic 21-day treatment with (R)-(-)-carvone (100mg/kg), (S)-(+)-carvone (100mg/kg), and lithium also prevented methylphenidate-induced hyperactivity. The present results suggest that carvone may have an antimanic-like effect.

  • A systematic review of the anxiolytic-like effects of essential oils in animal models
    Damião Pergentino De Sousa, Palloma De Almeida Soares Hocayen, Luciana Nalone Andrade and Roberto Andreatini

    Molecules, eISSN: 14203049, Pages: 18620-18660, Published: 14 October 2015 MDPI AG Postfach Basel CH-4005
    The clinical efficacy of standardized essential oils (such as Lavender officinalis), in treating anxiety disorders strongly suggests that these natural products are an important candidate source for new anxiolytic drugs. A systematic review of essential oils, their bioactive constituents, and anxiolytic-like activity is conducted. The essential oil with the best profile is Lavendula angustifolia, which has already been tested in controlled clinical trials with positive results. Citrus aurantium using different routes of administration also showed significant effects in several animal models, and was corroborated by different research groups. Other promising essential oils are Citrus sinensis and bergamot oil, which showed certain clinical anxiolytic actions; along with Achillea wilhemsii, Alpinia zerumbet, Citrus aurantium, and Spiranthera odoratissima, which, like Lavendula angustifolia, appear to exert anxiolytic-like effects without GABA/benzodiazepine activity, thus differing in their mechanisms of action from the benzodiazepines. The anxiolytic activity of 25 compounds commonly found in essential oils is also discussed.

  • Stretch, shrink, and shatter the rhythms: The intrinsic circadian period in mania and depression
    Bruno Jacson Martynhak, Marcela Pereira, Camila Pasquini de souza and Roberto Andreatini

    CNS and Neurological Disorders - Drug Targets, ISSN: 18715273, eISSN: 19963181, Pages: 963-969, Published: 1 October 2015 Bentham Science Publishers B.V.P.O. Box 294Bussum1400 AG
    Disturbances in the circadian rhythms have long been associated with depression and mania. Animal models of mania and depression exhibit differential effects upon the intrinsic circadian period and the same occurs with antidepressants and mood stabilizers treatment. The intrinsic circadian period is expressed when there are no time clues or when the light/dark cycle length is beyond the capacity of synchronization. In summary, while there is no clear association between the circadian period and mania, depressive-like behaviour is generally associated either with lengthening of the circadian period or with arrythmicity, and the improvement of depressive-like behaviour is associated with shortening of the circadian period. Thus, this review is an attempt to summarize data regarding these correlations and find a putative role of the circadian intrinsic period in mood regulation, particularly concerning the switch from depression to mania.

  • Assessment of anxiety in patients who undergo surgical procedures for tooth implants: a prospective study
    Milene Cardoso Candido, Roberto Andreatini, João Cesar Zielak, Juliana Feltrin de Souza and Estela Maris Losso

    Oral and Maxillofacial Surgery, ISSN: 18651550, eISSN: 18651569, Pages: 253-258, Published: 17 September 2015 Springer
    PurposeThe purpose of this study is to evaluate general anxiety using the State-Trait Anxiety Inventory (STAI) and dental anxiety using the Corah Dental Anxiety Scale (Corah-DAS) in patients who underwent surgical procedures for dental implants.MethodsThe study was performed with 55 patients who underwent implant surgery, of whom 37 were treated at a university and 18 were treated at a private office. General anxiety (STAI) and dental anxiety (Corah-DAS) were assessed at three different time points: appointment prior to clinical procedures (T1), day of procedures (just before the procedures; T2), and first post-procedure appointment (T3). The data were analyzed using analysis of variance followed by the Duncan test or Student’s t-test.ResultsState anxiety increased on the day of surgery (T2), whereas trait anxiety was higher at T1 (both p < 0.05). Women (n = 41) presented higher state anxiety at T2 than men (n = 14). Patients who were treated at the university (n = 37) exhibited higher state anxiety at both T1 and T3 than patients who were treated in a private practice (n = 18). Individuals with lower dental anxiety at T1 were those who reported having good experiences with dental treatment.ConclusionsAn increase in state anxiety was observed immediately before surgical procedures, and this increase was more pronounced in females. Although the Corah-DAS has been used as an indicator of dental anxiety, the STAI appears to be more sensitive for the measurement of anxiety. The application of appropriate methods is essential for ascertaining anxiety in patients, which should be considered in oral surgeries.

  • The nonsteroidal antiinflammatory drug piroxicam reverses the onset of depressive-like behavior in 6-OHDA animal model of Parkinson's disease
    Santiago, Tonin, Barbiero, Zaminelli, Boschen, Andreatini, Da Cunha, Lima and Vital

    Neuroscience, ISSN: 03064522, eISSN: 18737544, Volume: 300, Pages: 246-253, Published: August 06, 2015 Elsevier Ltd
    Depression is one of the most common psychiatric symptoms in patients with Parkinson's disease (PD). Some authors have reported that depression is characterized by activation of the inflammatory response. Animal models of PD also present with depressive-like behavior, such as increased immobility time in the modified forced swim test and anhedonia-like behavior in the sucrose preference test. Considering the potential neuroprotective effect of nonsteroidal antiinflammatory drugs in neurodegenerative diseases, the objective of the present study was to investigate the effects of piroxicam on depressive-like behavior in male Wistar rats lesioned with 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN). Antidepressant-like effects were observed after prolonged administration of piroxicam for 21days. In the forced swim test, the 6-OHDA+saline group exhibited significant reductions in swimming time and increased immobility time compared with the sham+saline. In the sucrose preference test, the 6-OHDA+piroxicam group exhibited no reduction of sucrose preference compared with the sham+saline, with significant effects of treatment and time and a significant treatment×time interaction. 5-Hydroxytryptamine (5-HT) levels significantly decreased in the hippocampus in the 6-OHDA+saline group and not changed in the 6-OHDA+piroxicam group when compared with the sham+saline on day 21. In conclusion, 21-day treatment with piroxicam reversed the onset of depressive-like behavior and prevented the reduction of hippocampal 5-HT levels.

  • Activation of postsynaptic D2 dopamine receptors in the rat dorsolateral striatum prevents the amnestic effect of systemically administered neuroleptics
    Suelen Lucio Boschen, Roberto Andreatini and Claudio da Cunha

    Behavioural Brain Research, ISSN: 01664328, eISSN: 18727549, Volume: 281, Pages: 283-289, Published: March 05, 2015 Elsevier
    Systemically administered antipsychotics bind to dopamine (DA) D2 receptors expressed in both pre- and postsynaptic neurons of different striatal sites and present an amnestic effect on learning and memory of conditioned avoidance responses (CAR). The aim of this study was to test whether blockade of the pre- or post-synaptic D2 receptors of the dorsolateral striatum of rats is the mechanism by which systemically administered antipsychotics present this amnestic effect. CAR learning and memory was evaluated in rats that received i.p. administrations of pre- or postsynaptic doses of the antipsychotic sulpiride combined with intra-DLS infusion of the D2 agonist quinpirole. Intra-DLS quinpirole itself was not amnestic and this effect was prevented by co-administration of presynaptic dose of sulpiride. However, sulpiride was amnestic when administered systemically in a post- but not presynaptic dose. This amnestic effect of sulpiride was prevented by the co-administration of quinpirole into the DLS. These results show that a blockade of postsynaptic D2 receptors in the DLS is necessary and sufficient to produce the amnestic effect of neuroleptics on CARs.

  • Social interaction with rat exposed to constant light during lactation prevents depressive-like behavior induced by constant light in adulthood
    Bruno Jacson Martynhak, Luiz Kae Sales Kanazawa, Guilherme Messias do Nascimento and Roberto Andreatini

    Neuroscience Letters, ISSN: 03043940, eISSN: 18727972, Volume: 588, Pages: 7-11, Published: February 09, 2015 Elsevier Ireland Ltd
    Circadian rhythm disruptions are often observed in depressed patients, and changes in the light/dark cycle promote depressive-like behavior in animal models. Prolonged exposure to constant light (LL) is known to lead to arrhythmicity of circadian locomotor activity and depressive-like behavior in rats. Interestingly, neonatal exposure to LL prevents both arrhythmicity and depressive behavior in adulthood. Arrhythmic rats under LL conditions that cohabitate with a rhythmic rat exhibit improvement in circadian rhythms. We tested whether such cohabitation also protects against LL-induced depressive-like behavior. Wistar rats were assigned to conditions of either neonatal constant light (neonatal-LL) on postnatal days 10-22 or a regular light/dark cycle (neonatal-LD). On day 45, the animals were assigned to three possible pair combinations. After a baseline sucrose preference test, half of the pairs were placed under LL conditions. Weekly sucrose preference tests were conducted to evaluate depressive-like behavior. The animals were isolated by an aluminum wall on the test day. At week 2 of LL, sucrose preference was reduced in neonatal-LD/neonatal-LD pairs of animals. At week 5, neonatal-LD/neonatal-LD pairs exhibited anhedonic-like behavior, but the pairs with at least one neonatal-LL rat did not. The LL cycle was returned to an LD cycle, and the neonatal-LD/neonatal-LD pairs exhibited a restoration of sucrose preference 2 weeks later. We conclude that social interaction can prevent depressive-like behavior induced by circadian rhythm disruption as long as one of the animals is more prone to present a strong rhythm.

  • 5-HT6 receptor agonism facilitates emotional learning
    Marcela Pereira, Bruno J. Martynhak, Roberto Andreatini and Per Svenningsson

    Frontiers in Pharmacology, eISSN: 16639812, Issue: SEP, Published: 2015 Frontiers Research
    Serotonin (5-HT) and its receptors play crucial roles in various aspects of mood and cognitive functions. However, the role of specific 5-HT receptors in these processes remains to be better understood. Here, we examined the effects of the selective and potent 5-HT6 agonist (WAY208466) on mood, anxiety and emotional learning in mice. Male C57Bl/6J mice were therefore tested in the forced swim test (FST), elevated plus-maze (EPM), and passive avoidance tests (PA), respectively. In a dose-response experiment, mice were treated intraperitoneally with WAY208466 at 3, 9, or 27 mg/kg and examined in an open field arena open field test (OFT) followed by the FST. 9 mg/kg of WAY208466 reduced immobility in the FST, without impairing the locomotion. Thus, the dose of 9 mg/kg was subsequently used for tests of anxiety and emotional learning. There was no significant effect of WAY208466 in the EPM. In the PA, mice were trained 30 min before the treatment with saline or WAY208466. Two separate sets of animals were used for short term memory (tested 1 h post-training) or long term memory (tested 24 h post-training). WAY208466 improved both short and long term memories, evaluated by the latency to enter the dark compartment, in the PA. The WAY208466-treated animals also showed more grooming and rearing in the light compartment. To better understand the molecular mechanisms and brain regions involved in the facilitation of emotional learning by WAY208466, we studied its effects on signal transduction and immediate early gene expression. WAY208466 increased the levels of phospho-Ser(845)-GluA1 and phospho-Ser(217/221)-MEK in the caudate-putamen. Levels of phospho-Thr(202/204)-Erk1/2 and the ratio mature BDNF/proBDNF were increased in the hippocampus. Moreover, WAY208466 increased c-fos in the hippocampus and Arc expression in both hippocampus and prefrontal cortex (PFC). The results indicate antidepressant efficacy and facilitation of emotional learning by 5-HT6 receptor agonism via mechanisms that promote neuronal plasticity in caudate putamen, hippocampus, and PFC.

  • The mechanism of antidepressant-like effects of piroxicam in rats
    Ronise Martins Santiago, Tiago Zaminelli, Taysa B. Bassani, Suelen L. Boschen, Marcelo M.S. Lima, Cláudio Da Cunha, Roberto Andreatini and Maria A.B.F. Vital

    Journal of Pharmacology and Pharmacotherapeutics, ISSN: 0976500X, eISSN: 09765018, Pages: 7-12, Published: 1 January 2015 Medknow PublicationsB9, Kanara Business Centre, off Link Road, Ghatkopar (E)Mumbai400 075
    OBJECTIVE To investigate the antidepressant-like effect of piroxicam with a focus on serotonergic neurotransmission. MATERIALS AND METHODS Rats were randomly distributed into the following groups: 0.9% saline control; 3 mg/kg pizotifen; 10 mg/kg sertraline; 10 mg/kg piroxicam; 10 mg/kg sertraline + 10 mg/kg piroxicam; 10 mg/kg sertraline + 3 mg/kg pizotifen; and 10 mg/kg piroxicam + 3 mg/kg pizotifen. All the drugs were dissolved in 0.9% saline. Three administrations of the drugs (piroxicam and sertraline) were performed 1, 5 and 24 h before testing the animals in the open field followed by the forced swim test (FST). Piroxicam and sertraline were administered orally by gavage and pizotifen was administered intraperitoneally 30 min before gavage. Immediately after the FST, the hippocampi were rapidly dissected for neurochemical analysis in high-performance liquid chromatography. RESULTS Acute treatment with piroxicam promoted an antidepressant-like effect in the FST, which was associated with an increase in serotonin levels in the hippocampus. This effect was potentiated in the piroxicam + sertraline group but counteracted by administration of the non-selective serotonin receptor antagonist pizotifen. CONCLUSION These results suggest that the antidepressant-like effect of piroxicam in the FST is mediated by the serotonin system; however, by different mechanisms from those of sertraline.

  • Induction of depressive-like behavior by intranigral 6-OHDA is directly correlated with deficits in striatal dopamine and hippocampal serotonin
    Ronise M. Santiago, Janaína Barbiero, Raisa W. Gradowski, Suelen Bochen, Marcelo M.S. Lima, Cláudio Da Cunha, Roberto Andreatini and Maria A.B.F. Vital

    Behavioural Brain Research, ISSN: 01664328, eISSN: 18727549, Volume: 259, Pages: 70-77, Published: 1 February 2014 Elsevier BV
    Among the non-motor phenomena of Parkinson's disease (PD) are depressive symptoms, with a prevalence of 40-70%. The reason for this high prevalence is not yet clear. The basal ganglia receives dopamine (DA) inputs from the substantia nigra pars compacta (SNpc), which is known to be impaired in PD patients. The neurotransmitter deficiency hypothesis of PD considers that low serotonin (5-hydroxytryptamine [5-HT]) activity in the brain in PD patients is a risk factor for depression. We investigated whether DA depletion promoted by the neurotoxin 6-hydroxydopamine (6-OHDA) is able to induce depressive-like behavior and neurotransmitter alterations that are similar to those observed in PD. To test this hypothesis, we performed intranigral injections of 6-OHDA in male Wistar rats and conducted motor behavior, depressive-like behavior, histological, and neurochemical tests. After the motor recovery period, 6-OHDA was able to produce anhedonia and behavioral despair 7, 14, and 21 days after neurotoxin infusion. These altered behavioral responses were accompanied by reductions of striatal DA. Additionally, decreases in hippocampal 5-HT content were detected in the 6-OHDA group. Notably, correlations were found between 5-HT and DA levels and swimming, immobility, and sucrose preference. Our results indicate that 6-OHDA produced depressive-like behavior accompanied by striatal DA and hippocampal 5-HT reductions. Moreover, DA and 5-HT levels were strongly correlated with "emotional" impairments, suggesting the important participation of these neurotransmitters in anhedonia and behavioral despair after 6-OHDA-induced nigral lesions.

  • Circadian fluctuation of reward response and synchronization to reward
    Bruno Jacson Martynhak and Roberto Andreatini

    Anhedonia: A Comprehensive Handbook Volume I: Conceptual Issues and Neurobiological Advances, Pages: 51-63, Published: 1 January 2014 Springer Netherlands
    Several physiological processes common to almost all living beings show fluctuations within the 24 h that compose the Earth’s light/dark cycle. Some examples of this in humans are the rise of cortisol levels early in the morning, the secretion on melatonin during the night and the core body temperature maxima and minima occurring during the late afternoon and late at night, respectively. Disruption of the circadian system can be one of the factors leading to depression and anhedonia. Alterations in circadian rhythms found in depressive patients include reduced amplitude of circadian rhythms, elevated temperature at night and early cortisol secretion. One feature of depression is diurnal variation in mood, which is generally worse during the morning and improves throughout the day. Moreover, the hedonic value of reward changes throughout the day and reward can synchronize circadian rhythms, as daily injections of methamphetamine can induce anticipation behavior. In this chapter, we will address the neurobiology of circadian rhythms, diurnal mood variation, fluctuating properties of reward over the 24 h cycle and, finally, the ability to synchronize circadian rhythms to reward regardless of the imposed light/dark cycle.

  • Amphetamine-induced appetitive 50-kHz calls in rats: A marker of affect in mania?
    Marcela Pereira, Roberto Andreatini, Rainer K. W. Schwarting and Juan C. Brenes

    Psychopharmacology, ISSN: 00333158, eISSN: 14322072, Volume: 231, Pages: 2567-2577, Published: April 2014 Springer Verlag
    RationaleAnimal models aimed to mimic mania have in common the lack of genuine affective parameters. Although rodent amphetamine-induced hyperlocomotion is a frequently used behavioral model of mania, locomotor activity is a rather unspecific target for developing new pharmacological therapies, and does not necessarily constitute a cardinal symptom in bipolar disorder (BD). Hence, alternative behavioral markers sensitive to stimulants are required.ObjectivesSince d-amphetamine induces appetitive 50-kHz ultrasonic vocalizations (USV) in rats, we asked whether established or potential antimanic drugs would inhibit this effect, thereby possibly complementing traditional analysis of locomotor activity.MethodsAmphetamine-treated rats (2.5 mg/kg) were systemically administered with the antimanic drugs lithium (100 mg/kg) and tamoxifen (1 mg/kg). Since protein kinase C (PKC) activity has been implicated in the pathophysiology of bipolar disorder and the biochemical effects of mood stabilizers, the new PKC inhibitor myricitrin (10, 30 mg/kg) was also evaluated.ResultsWe demonstrate for the first time that drugs with known or potential antimanic activity were effective in reversing amphetamine-induced appetitive 50-kHz calls. Treatments particularly normalized amphetamine-induced increases of frequency-modulated calls, a subtype presumably indicative of positive affect in the rat.ConclusionsOur findings suggest that amphetamine-induced 50-kHz calls might constitute a marker for communicating affect that provides a useful model of exaggerated euphoric mood and pressured speech. The antimanic-like effects of the PKC inhibitors tamoxifen and myricitrin support the predictive and etiological validity of both drugs in this model and highlight the role of PKC signaling as a promising target to treat mania and psychosis-related disorders.

  • Increased oxidative stress in prefrontal cortex and hippocampus is related to depressive-like behavior in streptozotocin-diabetic rats
    Helen de Morais, Camila P. de Souza, Luisa M. da Silva, Daniele M. Ferreira, Maria Fernanda Werner, Roberto Andreatini, Joice M. da Cunha and Janaina M. Zanoveli

    Behavioural Brain Research, ISSN: 01664328, eISSN: 18727549, Volume: 258, Pages: 52-64, Published: 1 January 2014 Elsevier BV
    Depression is a common comorbid in diabetic patients. The pathophysiologic mechanisms that relate this comorbidity is not completely elucidated yet, although several lines of evidence point out that increased oxidative stress resulting from hyperglycemia may have a crucial role. Thus, the effect of prolonged treatment with insulin (INS), the antioxidant vitamin E (VIT E) or the antidepressant imipramine (IMI) was evaluated in animals submitted to forced swimming test. Oxidative stress parameters (lipid peroxidation product levels, reduced gluthatione levels and catalase and superoxide dismutase activities) were also evaluated in brain areas related to depression, prefrontal cortex (PFC) and hippocampus (HIP). Our data show that treatment of streptozotocin-induced diabetic (DBT) rats with INS (6 UI/day, s.c.) prevented the blood glucose increase, reduced the immobility time, an antidepressant-like behavior, and normalized the reduced weight gain. Although the VIT E treatment (300 mg/kg, p.o.) had not altered the blood glucose levels, this treatment was able to reduce the immobility time and to reestablish the reduced weight gain in DBT rats. Differently, treatment with IMI (15 mg/kg, i.p.) induced antidepressant-like behavior in normoglycemic besides DBT animals. While VIT E and IMI treatments restored only specific oxidative stress parameters, INS was able to prevent all changed parameters evaluated in both PFC and HIP from DBT animals. Therefore, our data provide further evidence of the importance of oxidative stress in PFC and HIP in the pathophysiology of depression related to diabetes.

  • Neuroprotective and antidepressant-like effects of melatonin in a rotenone-induced Parkinson's disease model in rats
    Taysa B. Bassani, Raisa W. Gradowski, Tiago Zaminelli, Janaína K. Barbiero, Ronise M. Santiago, Suelen L. Boschen, Claudio Da Cunha, Marcelo M.S. Lima, Roberto Andreatini and Maria A.B.F. Vital

    Brain Research, ISSN: 00068993, eISSN: 18726240, Volume: 1593, Pages: 95-105, Published: 17 December 2014 Elsevier
    Parkinson׳s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Systemic and intranigral exposure to rotenone in rodents reproduces many of the pathological and behavioral features of PD in humans and thus has been used as an animal model of the disease. Melatonin is a neurohormone secreted by the pineal gland, which has several important physiological functions. It has been reported to be neuroprotective in some animal models of PD. The present study investigated the effects of prolonged melatonin treatment in rats previously exposed to rotenone. The animals were intraperitoneally treated for 10 days with rotenone (2.5mg/kg) or its vehicle. 24h later, they were intraperitoneally treated with melatonin (10mg/kg) or its vehicle for 28 days. One day after the last rotenone exposure, the animals exhibited hypolocomotion in the open field test, which spontaneously reversed at the last motor evaluation. We verified that prolonged melatonin treatment after dopaminergic lesion did not alter motor function but produced antidepressant-like effects in the forced swim test, prevented the rotenone-induced reduction of striatal dopamine, and partially prevented tyrosine hydroxylase immunoreactivity loss in the SNpc. Our results indicate that melatonin exerts neuroprotective and antidepressant-like effects in the rotenone model of PD.

  • Antidepressant-like effect of celecoxib piroxicam in rat models of depression
    Ronise M. Santiago, Janaína Barbiero, Bruno J. Martynhak, Suelen L. Boschen, Luisa M. Da Silva, Maria F. P. Werner, Claudio Da Cunha, Roberto Andreatini, Marcelo M. S. Lima and Maria A. B. F. Vital

    Journal of Neural Transmission, ISSN: 03009564, eISSN: 14351463, Volume: 121, Pages: 671-682, Published: June 2014 Springer-Verlag Wien
    Beyond the current hypothesis of depression, several new biological substrates have been proposed for this disorder. The present study investigated whether the anti-inflammatory drugs celecoxib and piroxicam have antidepressant activity in animal models of depression. After acute administration, we observed antidepressant-like effects of celecoxib (10 mg/kg) and piroxicam (10 mg/kg) in the modified forced swim test in rats. Piroxicam increased serotonin and norepinephrine levels in the hippocampus. Prolonged (21-day) treatment with celecoxib (10 mg/kg) and piroxicam (10 mg/kg) rescued sucrose preference in a chronic mild stress model of depression. Additionally, the chronic mild stress-induced reduction of hippocampal glutathione was prevented by treatment with celecoxib and piroxicam. Superoxide dismutase in the hippocampus was increased after chronic mild stress compared with the non-stressed saline group. The non-stressed celecoxib and piroxicam groups and stressed piroxicam group exhibited an increase in hippocampal superoxide dismutase activity compared with the stressed saline group. Lipid hydroperoxide was increased in the stressed group treated with vehicle and non-stressed group treated with imipramine but not in the stressed groups treated with celecoxib and piroxicam. These results suggest that the antidepressant-like effects of anti-inflammatory drugs might be attributable to enhanced antioxidant defenses and attenuated oxidative stress in the hippocampus.

  • The antimanic-like effect of phenytoin and carbamazepine on methylphenidate-induced hyperlocomotion: Role of voltage-gated sodium channels
    Denise A.G. Tonelli, Marcela Pereira, Isadora P. Siba, Bruno J. Martynhak, Diego Correia, Plínio C. Casarotto, Caroline Biojone, Francisco S. Guimarães, Samia L.R. Joca and Roberto Andreatini

    Fundamental and Clinical Pharmacology, ISSN: 07673981, eISSN: 14728206, Pages: 650-655, Published: December 2013 Wiley
    The objective of this study was to verify whether phenytoin modifies methylphenidate-induced hyperlocomotion, an animal model for screening antimanic-like drugs, and also evaluate the effect of veratrine, a voltage-gated sodium channel opener, pretreatment on the effect of phenytoin in this model. Carbamazepine was used as a positive control. Methylphenidate (5 mg/kg, s.c.) increased open-field locomotion, and phenytoin (5-10 mg/kg, i.p.) and carbamazepine (20 mg/kg, i.p.) blocked this effect. Veratrine (0.4 mg/kg, s.c.) pretreatment reversed the effects of phenytoin (10 mg/kg, i.p.) and carbamazepine (20 mg/kg, i.p.). Phenytoin (1-50 mg/kg, i.p.) and carbamazepine (10-20 mg/kg i.p.) alone did not change spontaneous locomotor activity. These results indicate that voltage-gated sodium channels play an important role in antimanic-like effects of phenytoin and carbamazepine on psychostimulant-induced hyperlocomotion model.

  • The roles of the nucleus accumbens core, dorsomedial striatum, and dorsolateral striatum in learning: Performance and extinction of Pavlovian fear-conditioned responses and instrumental avoidance responses
    Etieli Wendler, Jessica C.C. Gaspar, Tatiana L. Ferreira, Janaína K. Barbiero, Roberto Andreatini, Maria A.B.F. Vital, Charles D. Blaha, Philip Winn and Claudio Da Cunha

    Neurobiology of Learning and Memory, ISSN: 10747427, eISSN: 10959564, Volume: 109, Pages: 27-36, Published: November 2013 Elsevier BV
    This study examined the effects of bilateral excitotoxic lesions of the nucleus accumbens core (NAc-co), dorsomedial striatum (DMS) or dorsolateral striatum (DLS) of rats on the learning and extinction of Pavlovian and instrumental components of conditioned avoidance responses (CARs). None of the lesions caused sensorimotor deficits that could affect locomotion. Lesions of the NAc-co, but not DMS or DLS, decreased unconditioned and conditioned freezing. The NAc-co and DLS lesioned rats learned the 2-way active avoidance task more slowly. These results suggest: (i) CARs depend on both Pavlovian and instrumental learning; (ii) learning the Pavlovian component of CARs depends on the NAc-co; learning the instrumental component of CARs depends on the DLS, NAc and DMS; (iii) although the NAc-co is also needed for learning the instrumental component, it is not clear whether it plays a role in learning the instrumental component per se or if it simply allows learning of the Pavlovian component which is a pre-condition for learning the instrumental component; (iv) we did not find evidence that the DMS and DLS play the same roles in habit and goal-directed aspects of the instrumental component of CARs as observed in appetitive motivated instrumental responding.

  • The relationship between dental anxiety in children, adolescents and their parents at dental environment
    Cristiane Meira Assunção, Estela Maris Losso, Roberto Andreatini and José Vitor Nogara De Menezes

    Journal of Indian Society of Pedodontics and Preventive Dentistry, ISSN: 09704388, eISSN: 19983905, Pages: 175-179, Published: July 2013 Medknow
    PURPOSE The aim of the present study was to compare trait anxiety and dental anxiety among children, adolescents and their parents. MATERIALS AND METHODS A cross-sectional study was conducted involving 100 patients from the Pediatric Dentistry Clinic of the Federal University of Parana (Brazil) between the ages of 8 and 17 years (mean age: 10.3; standard deviation: 2.03) and their parents, who responded to Corah's Dental Anxiety Scale (DAS) and the Trait Anxiety Scale. The data were analyzed using the Mann-Whitney test, analysis of variance and both Pearson's and Spearman's correlation coefficients. RESULTS Ninety percent of children and adolescents and 76% of the parents had moderate anxiety based on the DAS score. Seventy-four percent of children and adolescents and 72% of the parents had moderate anxiety based on the Trait Anxiety Scale score. The trait anxiety and dental anxiety scores were correlated among the adults (rs = 0.64) and children (r = 0.52), whereas no correlation between scores was found among the adolescents. Associations were also found between children's trait anxiety and the dental and trait anxiety of their parents (both r = 0.43). CONCLUSIONS A moderate degree of dental anxiety was prevalent among the children, adolescents and parents who took part in this investigation, with correlations demonstrated between some trait anxiety and dental anxiety scores.

  • Anosmia does not impair the anxiolytic-like effect of lavender essential oil inhalation in mice
    Lea R. Chioca, Valquíria D.C. Antunes, Marcelo M. Ferro, Estela M. Losso and Roberto Andreatini

    Life Sciences, ISSN: 00243205, eISSN: 18790631, Issue: 20-21, Pages: 971-975, Published: 30 May 2013 Elsevier BV
    AIM The inhalation of Lavandula angustifolia (lavender) essential oil has anxiolytic-like effects in animal models and humans, but its mechanism of action is still not fully understood. The inhalation of essential oils can induce anxiolytic effects through the central nervous system (e.g., lung absorption and bloodstream transport) or stimulation of the olfactory system and secondary activation of brain regions. Thus, the main objective of the present study was to evaluate whether the perception of lavender essential oil aroma, when inhaled, is necessary to obtain its anxiolytic-like effects in mice tested in the marble-burying test. MAIN METHODS Anosmia was induced by irrigating the nasal cavity with zinc gluconate+zinc acetate so that the mice could not detect odors in the olfactory discrimination test. The marble-burying test was used to evaluate the anxiolytic-like effects of inhaled lavender essential oil. KEY FINDINGS Anosmia did not interfere with the anxiolytic-like effect of lavender essential oil inhalation in the marble-burying test at concentrations of 2.5% (number of marbles buried: vehicle, 4.7±1.0; zinc, 6.2±2.2; p>0.10) and 5% (number of marbles buried: vehicle, 3.4±0.8; zinc, 4.3±0.9; p>0.10). Lavender essential oil at a concentration of 0.5% was ineffective. SIGNIFICANCE These results suggest that olfactory system activation is unlikely to participate in the anxiolytic-like effect of lavender essential oil inhalation.

  • Anxiolytic-like effect of lavender essential oil inhalation in mice: Participation of serotonergic but not GABAA/benzodiazepine neurotransmission
    Lea R. Chioca, Marcelo M. Ferro, Irinéia P. Baretta, Sara M. Oliveira, Cássia R. Silva, Juliano Ferreira, Estela M. Losso and Roberto Andreatini

    Journal of Ethnopharmacology, ISSN: 03788741, eISSN: 18727573, Volume: 147, Pages: 412-418, Published: 20 May 2013 Elsevier BV
    ETHNOPHARMACOLOGICAL RELEVANCE Lavandula angustifolia (lavender) inhalation has been used in folk medicine for the treatment of anxiety, and clinical and animal studies have corroborated its anxiolytic effect, although its mechanism of action is still not fully understood. AIMS OF THE STUDY The objective of the present study was to determine whether the GABAA/benzodiazepine complex or serotonin neurotransmission mediates the anxiolytic-like effect of lavender essential oil. MATERIALS AND METHODS Male Swiss mice were subjected to the marble-burying test after being exposed to the aroma of lavender essential oil (1-5%), amyl acetate (5%; used as a behaviorally neutral odor), or distilled water for 15 min via inhalation. Additionally, the effect of 5% lavender essential oil was also evaluated in mice subjected to the elevated plus maze. GABAA/benzodiazepine mediation was evaluated by pretreating the mice with the GABAA receptor antagonist picrotoxin before the marble burying test and [(3)H]flunitrazepam binding to the benzodiazepine site on the GABAA receptor. Serotonergic mediation was studied by pretreating the mice with O-methyl-[3H]-N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635), a serotonin 5-HT1A receptor antagonist before the marble burying test. We also evaluated changes in the pharmacologically induced serotonin syndrome and the effects of combined administration of subeffective doses of lavender essential oil and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). RESULTS Lavender essential oil (1-5%) decreased the number of marbles buried compared with the control and amyl acetate groups. In the elevated plus maze, 5% lavender essential oil inhalation increased the percentage of time spent on and number of entries into the open arms compared with controls. No effect was seen in the number of closed arm entries or number of beam interruptions in the automated activity chamber. Pretreatment with the GABAA receptor antagonist picrotoxin (0.5mg/kg) did not modify the behavioral effect of 5% lavender essential oil in the marble-burying test. Lavender essential oil also did not alter [(3)H]flunitrazepam binding to the benzodiazepine site on the GABAA receptor. Pretreatment with the serotonin 5-HT1A receptor antagonist WAY100635 (3mg/kg) blocked the anxiolytic-like effect of lavender essential oil and the 5-HT1A receptor agonist 8-OH-DPAT (3mg/kg). A combination of ineffective doses of 8-OH-DPAT (0.5mg/kg) and lavender essential oil (0.1%) reduced the number of marbles buried. Finally, 5% lavender essential oil attenuated the serotonin syndrome induced by 40 mg/kg fluoxetine plus 80 mg/kg 5-hydroxytryptophan. CONCLUSIONS These results indicate an important role for the serotonergic system in the anxiolytic-like effect of lavender essential oil.

  • Sodium fluoride does not alter sperm production or sperm morphology in rats
    Lea Rosa Chioca, Juliane Centeno Müller, Ana Cláudia Boareto, Roberto Andreatini and Paulo Roberto Dalsenter

    Brazilian Archives of Biology and Technology, ISSN: 15168913, eISSN: 16784324, Pages: 257-262, Published: 2012 FapUNIFESP (SciELO)
    The aim of the present study was to evaluate the effects of sodium fluoride (NaF) on the male reproductive system. Adult male rats were exposed to NaF in drinking water for 30 days at three concentrations: 1.54 (control, tap water), 50 and 100 ppm. Body and organ weights, daily sperm production, sperm number and morphology were investigated. No difference was observed on the sperm number and morphology among the groups, as well as body weight and organ absolute and relative weights. Overall, despite the presence of a mild degree of dental fluorosis in the higher dose group, the results indicated that exposure to NaF at the doses used in the present study did not adversely affect sperm production and morphology of male rats.

  • SKF 38393 reverses cocaine-conditioned place preference in mice
    Pamela Sabioni, Vânia D'Almeida, Monica L. Andersen, Roberto Andreatini and José C.F. Galduróz

    Neuroscience Letters, ISSN: 03043940, eISSN: 18727972, Volume: 513, Pages: 214-218, Published: 4 April 2012 Elsevier BV
    Cocaine is a psychotropic drug with a high potential for abuse due to its euphoric effects. Efforts to develop medications for the treatment of cocaine dependence have not been clinically successful. Some studies using animal models have shown positive effects of dopaminergic agents such as partial agonists of the dopamine D1 receptor. Thus, this study aimed to examine the effect of the dopamine D1 receptor partial agonist SKF 38393 on cocaine craving. Adult male C57BL/6J mice were injected with cocaine for 10 days in a conditioned place preference apparatus using a biased procedure and subsequently treated for three consecutive days with SKF 38393. The results showed that SKF 38393 was able to block the preference of cocaine-conditioned animals for the compartment paired with the drug without showing effects on locomotor activity. The results of this study suggest that partial activation of D1 dopamine receptors may be necessary for the development of pharmacotherapies for cocaine addiction.

  • Anxiolytic-like effects of acute and chronic treatment with Achillea millefolium L. extract
    Irinéia Paulina Baretta, Regiane Américo Felizardo, Vanessa Fávero Bimbato, Maísa Gonalves Jorge Dos Santos, Candida Aparecida Leite Kassuya, Arquimedes Gasparotto Junior, Cássia Regina Da Silva, Sara Marchesan De Oliveira, Juliano Ferreira and Roberto Andreatini

    Journal of Ethnopharmacology, ISSN: 03788741, eISSN: 18727573, Volume: 140, Pages: 46-54, Published: 6 March 2012 Elsevier BV
    ETHNOPHARMACOLOGICAL RELEVANCE Achillea millefolium L. (Asteraceae), known as yarrow ("mil folhas"), has been used as folk medicine for gastrointestinal disorders, inflammation, anxiety, and insomnia. AIM To evaluate the potential anxiolytic-like effect of hydroalcoholic extract of Achillea millefolium L. in animal models. METHODS The present study evaluated the effects of the hydroalcoholic extract from the aerial parts of Achillea millefolium L. in mice subjected to the elevated plus-maze, marble-burying, and open-field tests. Additionally, the GABA(A)/benzodiazepine (BDZ) mediation of the effects of Achillea millefolium was evaluated by pretreatment with the noncompetitive GABA(A) receptor antagonist picrotoxin and the BDZ antagonist flumazenil and by [(3)H]-flunitrazepam binding to the BDZ site on the GABA(A) receptor. RESULTS Achillea millefolium exerted anxiolytic-like effects in the elevated plus-maze and marble-burying test after acute and chronic (25 days) administration at doses that did not alter locomotor activity. This behavioral profile was similar to diazepam. The effects of Achillea millefolium in the elevated plus-maze were not altered by picrotoxin pretreatment but were partially blocked by flumazenil. Furthermore, Achillea millefolium did not induce any changes in [(3)H]-flunitrazepam binding. CONCLUSION The results indicate that the orally administered hydroalcoholic extract of Achillea millefolium L. exerted anxiolytic-like effects that likely were not mediated by GABA(A)/BDZ neurotransmission and did not present tolerance after short-term, repeated administration.

  • Successful Combined Therapy with Tamoxifen and Lithium in a Paradoxical Sleep Deprivation-Induced Mania Model
    Fernanda Armani, Monica L. Andersen, Roberto Andreatini, Roberto Frussa-Filho, Sergio Tufik and José Carlos Fernandes Galduróz

    CNS Neuroscience and Therapeutics, ISSN: 17555930, eISSN: 17555949, Pages: 119-125, Published: February 2012 Wiley
    BACKGROUND Previous studies have suggested that manic states and sleep deprivation could contribute to the pathophysiology of bipolar disorder (BD) through protein kinase C (PKC) signaling abnormalities. Moreover, adjunctive therapy has become a standard strategy in the management of BD patients who respond poorly to current pharmacological treatments. AIM Thus, the aim of this study was to investigate the possible involvement of PKC inhibition by tamoxifen both separately or in combination with lithium, in paradoxical sleep deprivation (PSD)-induced hyperactivity, one facet of mania-like behavior. MATERIALS & METHODS Adult male C57BL/6J mice were randomly distributed (n = 7/group) in 24-h PSD or control groups and injected intraperitoneally (i.p.) with vehicle, lithium (50, 100, or 150 mg/kg) or tamoxifen (0.5, 1.0, or 2.0 mg/kg - experiment 1). In a second experiment, mice were injected i.p. with vehicle or a combination of subeffective doses of lithium and tamoxifen. Animals were subjected to a protocol based on repetitive PSD conditions, followed by assessment of locomotion activity in the open-field task. RESULTS PSD significantly increased locomotor activity in both experiments. These behavioral changes were prevented by a treatment with lithium or tamoxifen, or a combined treatment with both lithium and tamoxifen. DISCUSSION Therefore, our findings suggest that lithium and tamoxifen exert reversal effects against PSD-induced hyperactivity in mice. CONCLUSION Furthermore, tamoxifen as an adjunct to lithium therapy provides support for an alternative treatment of individuals who either do not respond adequately or cannot tolerate the adverse effects associated with therapeutic doses of lithium.

  • Depression and the hypothalamic-pituitary-adrenal axis: Increasing the scope
    Roberto Andreatini

    Acta Neuropsychiatrica, ISSN: 09242708, eISSN: 16015215, Pages: 1-3, Published: February 2012 Cambridge University

  • Characterization of motor, depressive-like and neurochemical alterations induced by a short-term rotenone administration
    Lívia H. Morais, Marcelo M. S. Lima, Bruno J. Martynhak, Ronise Santiago, Tatiane T. Takahashi, Deborah Ariza, Janaína K. Barbiero, Roberto Andreatini and Maria A. B. F. Vital

    Pharmacological Reports, ISSN: 17341140, Pages: 1081-1090, Published: 2012 Elsevier B.V.
    BACKGROUND Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. However, several aspects remain unclear regarding the effects and the accuracy of rotenone as an animal model of Parkinson's disease (PD). In this study, we investigated the motor and depressive-like behaviors associated to neurochemical alterations induced by a novel protocol of rotenone administration. METHODS In the first experiment, we adopted the paw test to characterize an effective dose of rotenone able to promote nigrostriatal toxicity. In the second experiment, control and rotenone 2.5 mg/kg groups were injected (ip) for 10 consecutive days. RESULTS This test indicated that intraperitonial (ip) rotenone at 2.5 and 5.0 mg/kg promoted a significant neurotoxicity to striatum and nucleus accumbens. However, only 2.5 mg/kg of rotenone was associated to a negligible mortality rate. Open-field tests were conducted on 1, 7, 14 and 21 day after the last day of treatment and showed an important locomotor impairment, confined to 1 and 7 day. Besides, rotenone affected dopamine levels and increased its turnover in the striatum. Modified forced swim test (performed on 22 day) and sucrose preference test (performed on 14 and 21 day) demonstrated that rotenone produced impairments in the swimming and immobility. In parallel, increments in the serotonin and noradrenaline turnovers were observed in the striatum and hippocampus of the rotenone group. CONCLUSIONS These data suggest important participations of serotonin and noradrenaline in depressive-like behaviors induced by rotenone. Thus, it is proposed that the current rotenone protocol provides an improvement regarding the existing rotenonemodels of PD.

  • Neonatal exposure to constant light prevents anhedonia-like behavior induced by constant light exposure in adulthood
    Bruno J. Martynhak, Diego Correia, Lívia H. Morais, Paula Araujo, Monica L. Andersen, Marcelo M.S. Lima, Fernando M. Louzada and Roberto Andreatini

    Behavioural Brain Research, ISSN: 01664328, eISSN: 18727549, Volume: 222, Pages: 10-14, Published: 12 September 2011 Elsevier BV
    Depressive episodes are associated with disturbances in circadian rhythms, and constant illumination has been reported to induce depressive-like behavior in rodents. Rats kept in constant darkness express the endogenous circadian rhythm, and most animals under constant light conditions lose circadian locomotor rhythmicity. Exposure to constant light in rats during lactation was reported to prevent this loss of circadian rhythm in adulthood. Thus, the aim of the present study was to verify whether exposure to constant light during lactation prevents anhedonia-like behavior induced by constant light in adult rats. In experiment 1, we replicated the anhedonia-like effects of constant light in adult male rats. We showed that this effect is reversed by imipramine treatment in the drinking water. In experiment 2, we subjected rats to constant darkness (neonatal-DD), constant light (neonatal-LL) or to normal light/dark cycle (neonatal-LD) during the neonatal phase and evaluated them after constant light exposure in adulthood. The group exposed to constant light during the neonatal phase did not reduce their sucrose preference and exhibited greater locomotor activity than the other groups. The neonatal-DD group exhibited decreased sucrose preference earlier than controls and had higher serum corticosterone concentrations. Prevention of arrhythymicity might protect neonatal-LL rats from anhedonia-like behavior induced by constant light, whereas constant darkness during the neonatal phase rendered the neonatal-DD group more susceptible to depressive-like behavior. These results corroborate with the literature data indicating that circadian disruption may contribute in mood disorders and that early life stress can influence stress responsivity in adulthood.

  • Antimanic-like effect of tamoxifen is not reproduced by acute or chronic administration of medroxyprogesterone or clomiphene
    Marcela Pereira, Bruno Jacson Martynhak, Irinéia Paulina Baretta, Diego Correia, Isadora Pozzetti Siba and Roberto Andreatini

    Neuroscience Letters, ISSN: 03043940, eISSN: 18727972, Volume: 500, Pages: 95-98, Published: 15 August 2011 Elsevier BV
    Tamoxifen, a protein kinase C (PKC) inhibitor and antiestrogenic drug, has clinical antimanic effects and blocks psychostimulant-induced hyperlocomotion. Medroxyprogesterone (MPA), which has antiestrogenic effects, also exerts some clinical benefits in female manic patients and partially blocks amphetamine-induced hyperlocomotion, indicating that the antiestrogenic effect of tamoxifen could contribute to its antimanic effect. The present study evaluated the effect of acute and chronic (21 day) treatment of two antiestrogenic drugs, MPA and clomiphene (an estrogenic receptor antagonist), on methylphenidate (MPH, 5.0mg/kg)-induced hyperlocomotion in mice, an animal model of mania. Acute and chronic tamoxifen administration was used as a positive control. Acute and chronic tamoxifen (1.0mg/kg) administration blocked MPH-induced hyperlocomotion. Acute and chronic MPA (acute: 3.0 or 6.0mg/kg; chronic: 3.0mg/kg) and clomiphene (acute: 1.5 or 3.0mg/kg; chronic: 1.5mg/kg) treatment did not alter MPH-induced hyperlocomotion. These results indicate that tamoxifen exerts antimanic-like effects, and reduced estrogenic activity does not have antimanic-like effects in this psychostimulant-induced hyperlocomotion model. Therefore, the antiestrogenic effect of tamoxifen likely does not contribute to its antimanic effect, which may instead be related to its effect on PKC activity. Therefore, PKC inhibition may be associated with the antimanic effect of mood stabilizers.

  • Myricitrin, a nitric oxide and protein kinase C inhibitor, exerts antipsychotic-like effects in animal models
    Pereira, Siba, Chioca, Correia, Vital, Pizzolatti, Santos and Andreatini

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, eISSN: 18784216, Pages: 1636-1644, Published: 15 August 2011 Elsevier BV
    Myricitrin is a nitric oxide (NO) and protein kinase C (PKC) inhibitor that has central nervous system activity, including anxiolytic-like action. Nitric oxide inhibitors blocked the behavioral effects of apomorphine, suggesting an antipsychotic-like effect. Furthermore, PKC inhibition reduced psychotic symptoms in acute mania patients and blocked amphetamine-induced hyperlocomotion, suggesting a potential antipsychotic-like effect. The present study evaluated the effects of myricitrin in animal models that assess antipsychotic-like effects (apomorphine-induced stereotypy and climbing and the paw test) and extrapyramidal side effects (catalepsy test and paw test). Olanzapine was used as a positive control. 7-Nitroindazole (7-NI), a NOS inhibitor, and l-arginine, a NO precursor, were used to evaluate nitrergic modulation, and tamoxifen was used to test the effect of PKC inhibition. In mice, myricitrin dose-dependently and olanzapine blocked the stereotypy and climbing induced by apomorphine at doses that did not induce catalepsy. 7-Nitroindazole also blocked apomorphine-induced stereotypy and climbing, which were reversed by l-arginine pretreatment. l-arginine only attenuated the effects of myricitrin on apomorphine's effects. Tamoxifen also blocked apomorphine-induced stereotypy and climbing. In the paw test in rats, myricitrin and olanzapine increased hindlimb retraction time at doses that did not affect forelimb reaction time, whereas haloperidol affected both parameters at the same dose. Myricitrin did not induce catalepsy in the bar test. Tamoxifen did not affect hindlimb retraction time or forelimb retraction time, whereas 7-NI significantly increased hindlimb reaction time. Thus, myricitrin exhibited an antipsychotic-like profile at doses that did not induce catalepsy, and this effect may be related to nitrergic action.

  • Magnesium sulfate and sodium valproate block methylphenidate-induced hyperlocomotion, an animal model of mania
    Francisco J. Barbosa, Bernardete Hesse, Rodrigo B. De Almeida, Irinéia P. Baretta, Roseli Boerngen-Lacerda and Roberto Andreatini

    Pharmacological Reports, ISSN: 17341140, Pages: 64-70, Published: 2011 Elsevier B.V.
    Magnesium sulfate (MgSO4) is used to treat and prevent eclamptic seizures, and several anticonvulsant drugs (e.g., sodium valproate) are clinically effective antimanic drugs. Psychostimulant-induced hyperlocomotion has been proposed as an animal model for the study of antimanic drugs. The present study evaluated the effects of MgSO4 and sodium valproate (as a positive control) on hyperlocomotion induced by methylphenidate in mice. Acute MgSO4 (300-400 mg/kg), but not sodium valproate (100-300 mg/kg), prevented the increase in locomotor activity induced by methylphenidate (5.0 mg/kg). In contrast, repeated treatment (14 days) with valproate (300 mg/kg), but not MgSO4 (400 mg/kg), blocked methylphenidate-induced hyperlocomotion. Thus, acute MgSO4 exerted antimanic-like effects in this animal model.

  • Memory impairment induced by sodium fluoride is associated with changes in brain monoamine levels
    Marcela Pereira, Patrícia A. Dombrowski, Estela M. Losso, Lea R. Chioca, Cláudio Da Cunha and Roberto Andreatini

    Neurotoxicity Research, ISSN: 10298428, Pages: 55-62, Published: January 2011 Springer Science and Business Media LLC
    Previous studies suggest that sodium fluoride (NaF) can impair performance in some memory tasks, such as open-field habituation and two-way active avoidance. In the present study, we evaluated the effect of NaF intake (100 ppm in drinking water for 30 days) and its short-term (15 days) withdrawal on open-field habituation and brain monoamine level. Adult male rats were allocated to three groups: tap water (NaF 1.54 ppm) for 45 days (control group); 15 days of tap water followed by NaF for 30 days; and NaF for 30 days followed by 15 days of tap water. The results showed that NaF impairs open-field habituation and increases noradrenaline (NA) and serotonin (5-HT) in the striatum, hippocampus and neocortex. Dopamine (DA) increase was restricted to the striatum. Short-term NaF withdrawal did not reverse these NaF-induced changes, and both NaF treatments led to a mild fluorosis in rat incisors. No treatment effect was seen in body weight or fluid/water consumption. These results indicate that sodium fluoride induces memory impairment that outlasts short-term NaF withdrawal (2 weeks) and may be associated with NA and 5-HT increases in discrete brain regions.

  • Acute but not chronic administration of pioglitazone promoted behavioral and neurochemical protective effects in the MPTP model of Parkinson's disease
    Janaína K. Barbiero, Ronise M. Santiago, Marcelo M.S. Lima, Deborah Ariza, Lívia H. Morais, Roberto Andreatini, and Maria A.B.F. Vital

    Behavioural Brain Research, ISSN: 01664328, eISSN: 18727549, Volume: 216, Pages: 186-192, Published: 1 January 2011 Elsevier BV
    The present study investigated the neurochemical, motor and cognitive effects of pioglitazone in a rat model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the first experiment, we administered MPTP, and 1h later administered a single oral dose of pioglitazone (5, 15 and 30 mg/kg). The following day, we performed the open-field test and neurochemical dose response curve. We demonstrated that 30 mg/kg of pioglitazone was capable of restoring striatal dopamine (DA) concentrations and motor behaviors. A second experiment was conducted to test the effects of two protocols (acute and chronic) of pioglitazone (30 mg/kg) administration in the open-field test, two-way active avoidance task and in the DA and metabolites levels. The acute protocol consisted of a single oral administration 1 h after MPTP, whereas the chronic protocol was performed with daily administrations starting 1 h after MPTP and ending 22 days after that. Results showed that neither protocol was able to reverse the cognitive impairment promoted by MPTP. We also demonstrated that acute treatment generated some level of neuroprotection, as confirmed by the absence of DA reduction in the group treated with pioglitazone in comparison to the sham group. By contrast, chronic treatment leaded to a reduction of striatal DA, close to MPTP administration alone. These findings suggest that acute administration of pioglitazone (30 mg/kg) was more efficient in generating beneficial effects on motor behaviors and in striatal DA levels. Nevertheless, we failed to demonstrate that pioglitazone administration improved performance on a dopamine-related cognitive task after MPTP.

  • Medicinal plants for the treatment of generalized anxiety disorder: A review of controlled clinical studies
    Thalita Thais Faustino, Rodrigo Batista de Almeida, and Roberto Andreatini

    Revista Brasileira de Psiquiatria, ISSN: 15164446, Pages: 429-436, Published: December 2010 FapUNIFESP (SciELO)
    OBJETIVO: Revisar os estudos clínicos controlados sobre a efetividade de plantas medicinais/fitoterápicos no transtorno de ansiedade generalizada. MÉTODO: Realizou-se uma busca (Medline, Web of Science, SciELO, Biblioteca Cochrane) por artigos originais utilizando as palavras ["plant OR phytomed* OR extract OR herbal OR medicinal (OR specific name plants)"] AND ("anxie* OR anxioly* OR tranquil* OR GAD"), delimitada a "human OR clinical trial OR randomized controlled trial OR meta-analysis OR review" e à língua inglesa. Os critérios de inclusão foram: estudos randomizados, comparativos e duplo-cegos. RESULTADOS: Foram selecionados sete dos 267 artigos encontrados. O Piper methysticum (kava-kava) foi o fitoterápico mais estudado, sendo sugerido um efeito ansiolítico. Entretanto, a maioria destes estudos incluiu outros transtornos de ansiedade e os dois estudos com transtorno de ansiedade generalizada apresentaram resultados contraditórios. Estudos isolados envolvendo Ginkgo biloba, Galphimia glauca, Matricaria recutita (camomila), Passiflora incarnata e Valeriana officinalis indicaram potencial efeito ansiolítico no transtorno de ansiedade generalizada. A Ginkgo biloba e a Matricaria recutita apresentaram um effect size ('d' de Cohen = 0,47 e 0,87) similar ou superior ao dos ansiolíticos atuais (0,17-0,38). Não foram localizados estudos com outras plantas. CONCLUSÃO: Apesar do potencial terapêutico dos fitoterápicos no transtorno de ansiedade generalizada, poucos ensaios clínicos controlados foram identificados, com a maioria apresentando limitações metodológicas.

  • The combination of Passiflora alata and Valeriana officinalis on memory tasks in mice: Comparison with diazepam
    Helvo Slomp Junior, Gerusa Seniski, Cláudio da Cunha, Elizabeth Aparecida Audi, and Roberto Andreatini

    Brazilian Archives of Biology and Technology, ISSN: 15168913, eISSN: 15168913, Pages: 1343-1350, Published: November 2010 FapUNIFESP (SciELO)
    The effect of a compound combining Valeriana officinalis and Passiflora alata extracts was tested on two mouse memory models: habituation and step-through inhibitory avoidance. Diazepam (1.0 and 2.5 mg/kg) was used as a positive control. Acute diazepam (2.5 mg/kg) before training impaired the habituation and performance in the inhibitory avoidance. On the other hand, acute phytotherapeutic compound (40-160 mg/kg), also before the training session, did not alter mouse behavior in these models. Repeated (15 days) treatment with the compound also did not impair the habituation. At the doses used, no locomotor effect was found. Taken together, the results suggest that, contrary to diazepam, the anxiolytic Valeriana officinalis and Passiflora alata compound did not induce amnesia.

  • Spironolactone and low-dose dexamethasone enhance extinction of contextual fear conditioning
    Ester Mayumi Ninomiya, Bruno Jacson Martynhak, Janaina M. Zanoveli, Diego Correia, Cláudio da Cunha, and Roberto Andreatini

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 1229-1235, Published: October 2010 Elsevier BV
    Glucocorticoids play a role in memory formation, and they may contribute to memory changes in stress-related mental disorders, such as posttraumatic stress disorder. Cortisol may act through mineralocorticoid (MR) or glucocorticoid (GR) receptors, and the objective of the present study was to evaluate the effects of the MR antagonist spironolactone, the GR antagonist mifepristone, the MR agonist fludrocortisone, and the GR agonist dexamethasone on the extinction of contextually conditioned fear in rats. Propranolol was used as a positive control. As expected, propranolol administered before the test session increased memory extinction. Pre-test administration of spironolactone and low-dose dexamethasone also increased the extinction of an aversive memory, whereas fludrocortisone impaired extinction. High-dose dexamethasone and mifepristone were found to have no effect in this model. Post-test spironolactone treatment impaired aversive memory extinction. These results indicate that MR and GR are related to extinction of aversive memories, and MR blockade may be a promising candidate for the treatment of stress-related memory disorders.

  • Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine
    Ronise M. Santiago, Janaína Barbieiro, Marcelo M.S. Lima, Patrícia A. Dombrowski, Roberto Andreatini, and Maria A.B.F. Vital

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 1104-1114, Published: August 2010 Elsevier BV
    Depression is a frequently encountered non-motor feature of Parkinson's disease (PD) and it can have a significant impact on patient's quality of life. Considering the differential pathophysiology of depression in PD, it prompts the idea that a degenerated nigrostriatal system plays a role in depressive-like behaviors, whilst animal models of PD are employed. Therefore, we addressed the question of whether dopamine (DA) depletion, promoted by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), lipopolysaccharide (LPS) and rotenone are able to induce depressive-like behaviors and neurotransmitters alterations similarly that encountered in PD. To test this rationale, we performed intranigral injections of each neurotoxin, followed by motor behavior, depressive-like behaviors, histological and neurochemical tests. After the motor recovery period, MPTP, 6-OHDA and rotenone were able to produce anhedonia and behavioral despair. These altered behavioral responses were accompanied by reductions of striatal DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) restricted to the 6-OHDA group. Additionally, decreases on the hippocampal serotonin (5-HT) content were detected for the MPTP, 6-OHDA and rotenone groups. Notably, strong correlations were detected among the groups when 5-HT and DA were correlated with swimming (r=+0.97; P=0.001) and immobility (r=-0.90; P=0.012), respectively. Our data indicate that MPTP, 6-OHDA and rotenone, but not LPS were able to produce depressive-like behaviors accompanied primarily by hippocampal 5-HT reductions. Moreover, DA and 5-HT strongly correlated with "emotional" impairments suggesting an important participation of these neurotransmitters in anhedonia and behavioral despair after nigral lesions promoted by the neurotoxins.

  • Non-motor function of the midbrain dopaminergic neurons
    Journal of Neural Transmission, Supplementa, ISSN: 03036995, Pages: 147-160, Published: 2009

  • The antimanic-like effect of tamoxifen: Behavioural comparison with other PKC-inhibiting and antiestrogenic drugs
    Pamela Sabioni, Irinéia P. Baretta, Ester M. Ninomiya, Lianna Gustafson, Ana Lúcia S. Rodrigues, and Roberto Andreatini

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 1927-1931, Published: 12 December 2008 Elsevier BV
    Protein kinase C (PKC) is an important cellular target for mood stabilizers such as lithium and valproate, and tamoxifen, an antiestrogenic drug with PKC inhibition activity, also demonstrates an antimanic effect. Thus, the aim of the present study was to evaluate whether the antimanic effect of tamoxifen is mediated through the PKC inhibitory and/or the antiestrogenic action(s) of the drug. In the present study, the effects of tamoxifen, chelerythrine (a PKC inhibitor) and medroxyprogesterone (an antiestrogenic drug) were investigated in amphetamine-induced hyperlocomotion of mice, an animal model of a manic state. Lithium carbonate (100 and 150 mg/kg, i.p.), tamoxifen (1.0 mg/kg, i.p.) and chelerythrine (1 microg/site, i.c.v.) completely blocked the amphetamine-induced hyperlocomotion. However, while the intermediate medroxyprogesterone dose (3.0 mg/kg, i.p.) partially reduced the amphetamine-induced hyperlocomotion, lower (1.0 mg/g) and higher (6.0 mg/kg) doses produced no effect. Our results indicate a major role for PKC inhibition in the antimanic-like effect of tamoxifen, although its antiestrogenic action may also contribute to this effect.

  • Depression in Parkinson's disease: A double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation
    Ticyana Moralez da Silva, Renato Puppi Munhoz, Cristiano Alvarez, Katya Naliwaiko, Ágata Kiss, Roberto Andreatini, and Anete Curte Ferraz

    Journal of Affective Disorders, ISSN: 01650327, Volume: 111, Issue: 2-3, Pages: 351-359, Published: December 2008 Elsevier BV
    BACKGROUND Effect of fish oil supplementation in parkinsonian patients with depression measured by Montgomery-Asberg Rating Scale (MADRS), the Clinical Global Impressions Scale (CGI) and Beck Depression Inventory (BECK). METHOD Double-blind, placebo-controlled study analyzed depression in 31 patients with Parkinson's Disease and Major Depression (DSM-IV). The patients were double-blind separated in 2 groups that received fish oil (containing omega-3 fatty acids) or mineral oil capsules for 3 months; each group was separated in 2 new groups: one taking antidepressant medication and another one not taking it. RESULTS 29 patients completed the 12-week trial, 58% were female and the mean age was 64.4 years old. Patients supplemented with fish oil showed a significant decrease in MADRS and CGI-Depression scores, and there was no difference among groups in BDI. 14 patients (42%) met criteria for > or = 50% reduction in MADRS score, 7 patients (22%) met criteria for remission (final MADRS total score < or = 12), and 2 patients (6%) discontinued supplementation of fish oil. HPLC analysis of fatty-acid profile showed increase of omega-3 fatty acid in the erythrocyte membrane of patients taking fish oil. CONCLUSION These results reveal that PD patients taking fish oil, with or without antidepressants, presented improvement in depressive symptoms and indicate that the intake of omega-3 can be used with an antidepressant effect or as adjuvant therapy with some other medication. This is a first pilot study with parkinsonian patients and omega-3 supplementation and requires replication in a larger sample.

  • Anxiolytic-like effect of chronic treatment with Erythrina velutina extract in the elevated plus-maze test
    I.M. Raupp, A. Sereniki, S. Virtuoso, C. Ghislandi, E.L. Cavalcanti e Silva, H.A. Trebien, O.G. Miguel, and R. Andreatini

    Journal of Ethnopharmacology, ISSN: 03788741, Volume: 118, Pages: 295-299, Published: 23 July 2008 Elsevier BV
    INTRODUCTION In Brazil, Erythrina velutina (Fabaceae) is widely used as a tranquilizer and/or sedative, and its extract exerts an anxiolytic-like effect profile in animal models, although these results may be caused by its sedative or amnesic effects. AIMS, MATERIALS AND METHODS: Thus, this study evaluated the effect of acute and chronic (23-26 days) administrations of the hydroalcoholic extract of the stem bark of Erythrina velutina (orally) in mice submitted to the following tests: elevated plus-maze, forced swim, spontaneous locomotor activity, and habituation to active chamber. Chlordiazepoxide and imipramine were used as standard drugs. RESULTS In the elevated plus-maze test, chronic, but not acute, Erythrina velutina (100mg/kg) administration increased the percentage of open arm entries, an effect also seen in both acute and chronic treatments with chlordiazepoxide (7.5mg/kg). In the forced swim test, only imipramine (25mg/kg) decreased immobility time. Impairment of habituation was seen only with acute imipramine administration and with the lowest doses of Erythrina velutina extract tested in acute (10mg/kg) and chronic (50mg/kg) administrations. CONCLUSIONS These results suggest that chronic administration of the hydroalcoholic extract of the stem bark of Erythrina velutina exerts an anxiolytic-like effect on mice, and it could serve as a new approach for the treatment anxiety, although it may have an amnesic effect at low doses.

  • The elevated T-maze as a measure of two types of defensive reactions: A factor analysis
    José Carlos Miranda Torrejais, Camila Castilho Machado Rosa, Roseli Boerngen-Lacerda, and Roberto Andreatini

    Brain Research Bulletin, ISSN: 03619230, Pages: 376-379, Published: 1 July 2008 Elsevier BV
    Using factor analysis, we investigated whether the defensive reactions seen in the elevated T-maze measure different behaviours. Rats were submitted to the elevated T-maze followed by the open-field test. Avoidance 1 and 2 loaded on the same factor, while escape 2 and 3 loaded on a second factor. Baseline avoidance did not load together with locomotor activity in the open-field. These results indicate that the elevated T-maze generates two different defensive behaviours.

  • Repeated intranigral MPTP administration: A new protocol of prolonged locomotor impairment mimicking Parkinson's disease
    Angela Braga Reksidler, Marcelo Meira Santos Lima, Patrícia Dombrowski, Monica Levy Andersen, Sílvio Marques Zanata, Roberto Andreatini, Sergio Tufik, and Maria Aparecida Barbato Frazão Vital

    Journal of Neuroscience Methods, ISSN: 01650270, Volume: 167, Pages: 268-277, Published: 30 January 2008 Elsevier BV
    Different Parkinson's disease (PD) animal models reproduce the early phase of the disease, which deny the possible existence of a synergic effect of consecutive insults to the dopaminergic neurons. We proposed a novel protocol of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) nigrostriatal lesion, which consists in repeated MPTP intranigral administrations intending to differentiate effects of a single lesion in relation to repeated lesions. For this purpose, a schedule of 3-day intervals between the MPTP administrations, totalizing 3 infusions in 9 days were adopted. A persistent locomotor deficit was produced after the 2nd infusion, remaining until the last time-point. Tyrosine hydroxylase (TH) immunoreactive neurons were reduced in 50% 1 day after the 1st infusion and the neuronal loss remained constant even after the 2nd and 3rd MPTP infusions. In parallel, (TH) protein expression in the substantia nigra pars compacta (SNpc) revealed to be a sensitive target for MPTP, once it was found to be down-regulated immediately after the 1st MPTP exposure until the last time-point. These findings corroborate the concept of an early phase model of PD elicited by MPTP even when this neurotoxin was used according to the protocol currently proposed. The current protocol provided relevant insights about TH expression and irreversible locomotor impairment.

  • Subchronic fluoride intake induces impairment in habituation and active avoidance tasks in rats
    Lea R. Chioca, Inara M. Raupp, Cláudio Da Cunha, Estela M. Losso, and Roberto Andreatini

    European Journal of Pharmacology, ISSN: 00142999, Volume: 579, Issue: 1-3, Pages: 196-201, Published: 28 January 2008 Elsevier BV
    Since clinical case reports suggest that sodium fluoride (NaF) intoxication may impair learning and memory, the objective of the present study was to evaluate the effects of NaF on two memory tasks: open-field habituation and two-way active avoidance. Adult male rats were exposed to NaF in drinking water at three concentrations for 30 days: 1.54 (control, tap water), 50 and 100 ppm NaF (corresponding to an intake of 0.10+/-0.005, 5.15+/-0.14, and 10.77+/-0.39 mg/kg of NaF, respectively). At day 30, the rats were placed in an open-field and retested after 24 h (test session) to measure habituation. In the two-way active avoidance task, another three groups of rats were trained in a 30-trial training session and tested again 24 h later (test session). Dental fluorosis was also evaluated. Habituation was impaired by 50 and 100 ppm, but not by 1.54 ppm NaF. Moreover, 100 ppm NaF reduced the number of avoidance responses in the active avoidance task. No locomotor impairment was observed. Mild dental fluorosis in rat incisor teeth was found in the 50 and 100 ppm NaF groups. Overall, these results suggest that moderate intoxication with sodium fluoride has potentially deleterious effects on learning and memory.

  • Repeated paroxetine treatment reverses anhedonia induced in rats by chronic mild stress or dexamethasone
    P.C. Casarotto and R. Andreatini

    European Neuropsychopharmacology, ISSN: 0924977X, Pages: 735-742, Published: November 2007 Elsevier BV
    The present study was designed to assess the effect of dexamethasone, a synthetic glucocorticoid receptor agonist, in the sucrose preference test in rats. Rats treated acutely with dexamethasone (5-10 mg/kg) showed a significant decrease in sucrose preference (anhedonia) in comparison to vehicle treated rats, although 1 mg/kg dexamethasone did not alter the sucrose preference. Daily paroxetine treatment (10 g/kg, i.p., 14 days) reversed the anhedonic effect of acute dexamethasone (5 mg/kg), while causing no increased sucrose preference in rats that received dexamethasone vehicle. The paroxetine vehicle treated rats showed anhedonia even 14 days after acute dexamethasone administration. Paroxetine (10 mk/kg, i.p. for 28 days) also reversed anhedonia induced by chronic mild stress (8 weeks). In conclusion, acute dexamethasone induced an enduring anhedonic state that was reversed by repeated paroxetine treatment. Thus, the present study adds new data to the evidence supporting an important role for glucocorticoid in depression.

  • Veratrine blocks the lamotrigine-induced swimming increase and immobility decrease in the modified forced swimming test
    F.T. Codagnone, F.T. Consoni, A.L.S. Rodrigues, M.A.B.F. Vital, and R. Andreatini

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 1307-1311, Published: 15 August 2007 Elsevier BV
    Lamotrigine exhibits an anti-immobility effect in the modified forced swimming test, increasing swimming and climbing, behaviors that are related to serotonergic and noradrenergic effects, respectively. However, these effects could be secondary to lamotrigine blockade of Na(+) sensitive channel. Thus, this study investigated the influence of veratrine (0.1 mg/kg, ip, 10 min before each lamotrigine administration), an Na(+) channel activator, in the effect of lamotrigine (20 mg/kg, ip, 24, 5, 1 h before the test session) in the modified forced swimming test. Veratrine pre-treatment blocked lamotrigine-induced immobility decrease and swimming increase but it did not change the effect of lamotrigine on climbing. These results suggest that the serotonergic effect of lamotrigine in the modified forced swimming test is dependent on Na(+) voltage sensitive channel blockade, whereas its noradrenergic effect is not.

  • Antidepressant-like effect of lamotrigine in the mouse forced swimming test: Evidence for the involvement of the noradrenergic system
    Manuella Pinto Kaster, Inara Raupp, Ricardo Wabner Binfaré, Roberto Andreatini, and Ana Lúcia S. Rodrigues

    European Journal of Pharmacology, ISSN: 00142999, Volume: 565, Issue: 1-3, Pages: 119-124, Published: 22 June 2007 Elsevier BV
    Lamotrigine is an anticonvulsant drug that is also effective in the treatment of mood disorders, especially bipolar disorder. However, few studies have been conducted in animal models of depression to evaluate its mechanism of action. The present study investigated the effect of lamotrigine in the forced swimming test in mice and the involvement of the noradrenergic system in this effect. Lamotrigine (20-30 mg/kg, i.p.) decreased the immobility time in the forced swimming test and the number of crossings in the open-field test. In addition, the pretreatment of mice with the inhibitor of the enzyme tyrosine hydroxylase, alpha-methyl-p-tyrosine (100 or 250 mg/kg), prevented the antidepressant-like effect of lamotrigine (30 mg/kg, i.p.) in the forced swimming test. Besides that, the pretreatment of mice with prazosin (1 mg/kg, i.p., an alpha1-adrenoceptor antagonist) or yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist) also prevented the anti-immobility effect of lamotrigine (30 mg/kg, i.p.). Moreover, the administration of subeffective doses of phenylephrine (5 mg/kg, i.p., an alpha1-adrenoceptor agonist) or clonidine (0.06 mg/kg, i.p., an alpha2-adrenoceptor agonist) was able to potentiate the action of a subeffective dose of lamotrigine (10 mg/kg, i.p.) in the forced swimming test. Thus, the present study suggests that the antidepressant-like effect of lamotrigine in the forced swimming test is related to the noradrenergic system, likely due to an activation of alpha1- and alpha2-postsynaptic adrenoceptors.

  • Pre-training to find a hidden platform in the Morris water maze can compensate for a deficit to find a cued platform in a rat model of Parkinson's disease
    Claudio Da Cunha, Samantha Wietzikoski, Evellyn C. Wietzikoski, Marcio H.C. Silva, Jeff Chandler, Marcelo M. Ferro, Roberto Andreatini, and Newton S. Canteras

    Neurobiology of Learning and Memory, ISSN: 10747427, Pages: 451-463, Published: May 2007 Elsevier BV
    The bilateral intranigral infusion of 1 micromol 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in adult male Wistar rats caused a specific and partial loss of substantia nigra pars compacta (SNc) dopamine neurons, a partial depletion of striatal dopamine, and a deficit to learn the intra-maze cued version of the Morris water maze. Pre-training the SNc rats in the spatial version of the water maze or simply maintaining the animals on the water maze platform reversed this deficit. This improvement was even observed when the order of the extra-maze cues presented to the rats during pre-training of the spatial version was changed during training of the intra-maze cued version. However, this deficit was not reversed either by maintaining the animals on the platform if the spatial cues were surrounded and covered with a curtain or by swimming sessions in the maze without the escape platform and the curtain. These findings suggest that none of the following elements alone, learned during the spatial task pre-training, could help SNc rats learn the intra-maze cued task: improvement of swimming skills or knowledge of the existence of the escape platform; distance between the platform and the border of the pool; location of a particular extra-maze cue; relations among extra-maze cues. However, the simultaneous presence of the escape platform and extra-maze cues (irrespective of their relational configuration) during the pre-training sessions proved to be necessary for this improving effect to occur.

  • The COX-2 inhibitor parecoxib produces neuroprotective effects in MPTP-lesioned rats
    Angela B. Reksidler, Marcelo M.S. Lima, Sílvio M. Zanata, Hidevaldo B. Machado, Cláudio da Cunha, Roberto Andreatini, Sergio Tufik, and Maria A.B.F. Vital

    European Journal of Pharmacology, ISSN: 00142999, Volume: 560, Issue: 2-3, Pages: 163-175, Published: 10 April 2007 Elsevier BV
    The present study investigated the effects of the selective cyclooxygenase-2 (COX-2) inhibitor parecoxib (Bextratrade mark) in the prevention of motor and cognitive impairments observed in rats after an intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a model of the early phase of Parkinson's disease. The treatment with parecoxib (10 mg/kg) administered prior to the surgery and daily (2 mg/kg) for the subsequent 21 days, prevented the MPTP-treated rats from presenting decreased locomotor and exploratory behavior, increased immobility, and impairment while performing the cued version of the Morris water maze. Furthermore, parecoxib treatment also significantly prevented the reduction of tyrosine hydroxylase protein expression in the substantia nigra (7, 14 and 21 days after surgery), and in the striatum (14 and 21 days after surgery) as immunodetected by western blotting. These results strongly suggest that parecoxib exerts a neuroprotective effect on motor, tyrosine hydroxylase expression, and cognitive functions as it prevents their impairments within the confines of this animal model of the early phase of Parkinson's disease.

  • Amphetamine and pentylenetetrazole given post-trial 1 enhance one-trial tolerance to the anxiolytic effect of diazepam in the elevated plus-maze in mice
    Kleber Meneghel Vargas, Cláudio Da Cunha, and Roberto Andreatini

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 1394-1402, Published: 30 December 2006 Elsevier BV
    There are several hypotheses to explain the lack of an anxiolytic effect on animals with previous maze experience (one-trial tolerance). Some of these hypotheses are related to learning and memory, so the reduction of trial 1 duration to 1 min or amnesic drug administration before trial 1 prevents the lack of an anxiolytic effect in trial 2. Amphetamine and pentylenetetrazole have been shown to enhance memory consolidation when administered immediately after training. Thus, the aim of the present study was to evaluate the effect of amphetamine (1.0-3.0 mg/kg) or pentylenetetrazole (30.0 mg/kg), at putative memory-enhancing doses, on the effect of diazepam (2.5 mg/kg) in the elevated plus-maze trial 2 on mice exposed to a 1-min long trial 1. Mice were submitted to 1-min trial 1 in the elevated plus-maze immediately followed by drug treatment (saline, amphetamine, or pentylenetetrazole) and to elevated plus-maze trial 2 after 48 h. Animals were treated with vehicle or diazepam 30 min before trial 2. The results showed that post-trial 1 saline and 1.0 mg/kg amphetamine did not induce one-trial tolerance. On the other hand, 2.0 and 3.0 mg/kg amphetamine and 30 mg/kg pentylenetetrazole induced a lack of anxiolytic effect of diazepam on trial 2 even with 1-min trial 1 length. Furthermore, these data were not due to novelty exposure in trial 1 or to amphetamine treatment so that mice exposed to an activity chamber instead of the plus-maze (trial 1) and then immediately submitted to amphetamine treatment (2.0 mg/kg) did not show one-trial tolerance 48 h after trial 1. Taken as a whole, these data support the hypothesis that memory is involved in the lack of an anxiolytic effect in the elevated plus-maze trial 2.

  • Reversible inactivation of the dorsal raphe nucleus blocked the antipanic-like effect of chronic imipramine in the elevated T-maze
    Patrícia Andréia Dombrowski and Roberto Andreatini

    Neuroscience Letters, ISSN: 03043940, Volume: 407, Pages: 80-85, Published: 16 October 2006 Elsevier BV
    Antidepressant drugs are effective in the treatment of panic in human panic disorder patients. One hypothesis is that the anti-panic effects of antidepressant drugs are mediated by an increase in the activity of serotonergic neurons within dorsal raphe nucleus (DRN) leading to an increase in serotonin-mediated inhibition of the dorsal periaqueductal gray (DPAG). In order to test this hypothesis, we investigated the effects of reversible inhibition of the DRN on behavior in the elevated T-maze (ETM) in control rats and rats chronically treated with imipramine. Rats were injected daily with imipramine (15 mg/kg i.p.) or saline for 24 days. A guide cannula was implanted in the DRN on day 14. Lidocaine (4%, 0.2 microL) or saline was injected into the DRN 10 min before the test in the ETM followed immediately by the open-field test (day 21). Three days later, the infusions were crossed-over, rats microinjected into the DRN with saline in the first trial received lidocaine and vice versa, and the behavioral tests were repeated (day 24). Chronic saline plus lidocaine in the DRN and chronic imipramine (plus saline or lidocaine in the DRN) impaired inhibitory avoidance, indicating an anxiolytic effect. In the one-way escape, lidocaine facilitated it, suggesting a panicogenic effect, while chronic imipramine impaired it, which is indicative of a panicolytic effect. Moreover, lidocaine blocked the facilitatory effect of chronic imipramine. The locomotor activity in the open field was not changed by any treatment compared to the control group. These effects were congruent with the hypothesis that the DRN has a dual effect on anxiety: increasing learned anxiety and decreasing innate anxiety. Moreover, they suggest that the DRN exerts a crucial role in the antipanic-like effect of chronic imipramine in the ETM.

  • Dual monoamine modulation for the antidepressant-like effect of lamotrigine in the modified forced swimming test
    Fernando T. Consoni, Maria A.B.F. Vital, and Roberto Andreatini

    European Neuropsychopharmacology, ISSN: 0924977X, Pages: 451-458, Published: August 2006 Elsevier BV
    Lamotrigine is an anticonvulsant drug that exhibits a clinical antidepressant effect. However, few studies have been conducted with lamotrigine in animal models of depression and its mechanism of antidepressant action is still unclear. The present study evaluates the effect of lamotrigine (5-20mg/kg, i.p.) in the modified forced swimming test and compare its behavior pattern in the test with those of paroxetine (20mg/kg, i.p.), nortriptyline (20mg/kg, i.p.) and dizolcipine-MK-801 (0.1mg/kg, i.p.). The effect of lamotrigine on locomotor activity and memory was also studied in order to exclude false-positive results. At low doses, lamotrigine (10mg/kg) decreased immobility and increased climbing scores, a similar pattern to nortriptyline. A higher lamotrigine dose (20mg/kg) also increased swimming scores. Lamotrigine neither changed locomotion in the open-field test nor impaired habituation. Paroxetine and dizolcipine decreased immobility and increased swimming. Dizolcipine also decreased climbing. However, although the effects of paroxetine and nortriptyline were seen without effect on locomotor activity, dizolcipine increased locomotor activity. The present study indicates that the antidepressant-like effect of lamotrigine is probably related to noradrenergic/serotonergic systems.

  • Picrotoxin blocks the anxiolytic- and panicolytic-like effects of sodium valproate in the rat elevated T-maze
    Patrícia A. Dombrowski, Lineane H. Fernandes, and Roberto Andreatini

    European Journal of Pharmacology, ISSN: 00142999, Volume: 537, Issue: 1-3, Pages: 72-76, Published: 10 May 2006 Elsevier BV
    The effect of acute sodium valproate administration, an anxiolytic and putative panicolytic drug, was evaluated in rats tested in the elevated T-maze, an animal model that measures two defensive reactions: avoidance (inhibitory avoidance), related to generalized anxiety, and escape (escape from open arms), related to panic. Additionally, the involvement of gamma-aminobutyric acid (GABA) neurotransmission in sodium valproate effects was studied by picrotoxin co-administration. Sodium valproate (300 mg/kg, intraperitoneally, 30 min before the test) impaired both avoidance latency (time to leave the closed arm) and one-way escape (latency to enter the closed arm) indicating anxiolytic and panicolytic effects, respectively. Pre-treatment with picrotoxin (0.5 mg/kg, intraperitoneally, 5 min before sodium valproate administration) blocked the effects of sodium valproate on inhibitory avoidance and one-way escape. No locomotor effect was seen in the open-field. These data suggest that sodium valproate exerts anxiolytic-like and panicolytic-like effects in the elevated T-maze and that these effects were mediated by picrotoxin-sensitive GABA type A receptors.

  • Different effects of 7-nitroindazole in reserpine-induced hypolocomotion in two strains of mice
    Meigy T. Tadaiesky, Roberto Andreatini, and Maria A.B.F. Vital

    European Journal of Pharmacology, ISSN: 00142999, Volume: 535, Issue: 1-3, Pages: 199-207, Published: 27 March 2006 Elsevier BV
    There are a number of reasons for believing that nitric oxide participates in motor control in the striatum. Therefore, effects of neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) were studied on the reserpine model of Parkinson's disease in Swiss and C57BL/6 mice using the open-field test. Mice received reserpine (1 mg/kg administered intraperitoneally). A significant hypolocomotion was observed 24 h and 48 h after reserpine injection. The treatment with 7-nitroindazole (25 mg/kg, administered intraperitoneally, 30 min after reserpine) attenuated reserpine-induced hypolocomotion 24 h and 48 h after the treatment in Swiss mice, but not completely in C57BL/6 mice. These results suggest that nitric oxide functions as an intercellular messenger in motor circuits in the brain. Moreover, our data suggests that the comparison of such mouse strains may provide information on genetic basis for strain differences in different sensitivity to these drugs.

  • Intra-nigral MPTP lesion in rats: Behavioral and autoradiography studies
    Juliana C. Perry, Débora C. Hipólide, Sergio Tufik, Ronan D. Martins, Cláudio Da Cunha, Roberto Andreatini, and Maria Aparecida B.F. Vital

    Experimental Neurology, ISSN: 00144886, Volume: 195, Pages: 322-329, Published: October 2005 Elsevier BV
    The present study investigated the motor response and possible changes in binding to D1 and D2 receptors after intra-nigral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) infusion on rats. The results indicated that MPTP-lesioned rats exhibited a significant reduction in locomotion and rearing frequencies observed in an open field 24 h after surgery. However, at 7 and 14 days after surgery the MPTP-lesioned rats showed a significant increase in locomotion in comparison to the control groups, as well as a decrease in immobility time. In addition, 21 days after surgery the behavioral measurements were unaltered by these procedures. Moreover, latency in initiating movement and catalepsy were unchanged by this neurotoxin on the same days of observation. An autoradiography approach indicated that there was a reduction in [3H]SCH 23390 binding in substantia nigra pars compacta (SNpc), substantia nigra pars reticulata (SNpr) and ventrolateral striatum in MPTP-treated rats 21 days after the surgery. [3H]raclopride binding remained unaltered by the MPTP treatment. These results suggest that compensatory plastic changes occur in D1 dopamine receptors after partial lesion of nigral dopaminergic neurons. These alterations might be related to the occurrence and recovery of motor impairment observed in MPTP-lesioned rats.

  • Anxiolytic and sedative effects of a combined extract of Passiflora alata Dryander and Valeriana officinalis L. in rats
    Acta Scientiarum - Health Sciences, ISSN: 16799291, Pages: 145-150, Published: July 2005

  • Phosphatidylserine: An antidepressive or a cognitive enhancer?
    João C. Castilho, Juliana C. Perry, Roberto Andreatini, and Maria A.B.F. Vital

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 731-738, Published: July 2004 Elsevier BV
    The aim of the present study was to evaluate the putative antidepressive and cognitive enhancer effects of phosphatidylserine (BC-PS). The antidepressive effect of BC-PS (50, 100 or 200 mg/kg), compared to saline or imipramine (IMI; 25 mg/kg), was studied in the forced swimming test in rats. These drugs were administered 1 and 8 h after training and 1 h before the test. BC-PS (50, 100 and 200 mg/kg)-treated rats exhibited a significant decrease in immobility time (IT) in the test session (performed 24 h after training) when compared to control rats. Moreover, the IMI-treated group showed a significant reduction in IT in comparison to control rats. The cognitive enhancer effect of BC-PS (50, 100 and 200 mg/kg) was studied in the three versions of the water maze task: spatial working memory version, spatial reference memory version, and cued version. There was no significant difference between the BC-PS-treated groups and control animals in these memory tasks. Taken together, the present results are suggestive of an antidepressive effect of BC-PS in the forced swimming test in rats but not of a cognitive enhancer effect of the drug in the water maze test.

  • Effect of Hypericum perforatum on marble-burying by mice
    L. L. Skalisz, V. Beijamini, and R. Andreatini

    Phytotherapy Research, ISSN: 0951418X, Pages: 399-402, Published: May 2004 Wiley
    The effect of Hypericum perforatum extract (LI 160) at a dose that exerts an antidepressive-like effect was studied in mice in the marble-burying test. Acute Hypericum perforatum (150, 300 and 500 mg/kg, p.o.) reduced immobility time in the forced swimming test. The number of marbles buried, but not locomotor activity, was reduced by acute treatment with Hypericum perforatum (150 and 300 mg/kg, p.o.). However, this effect was not seen after chronic treatment (21 days) with Hypericum perforatum (300 mg/kg, p.o.). Thus, Hypericum perforatum extract, at antidepressant dose, exerts an acute anxiolytic drug effect on the marble-burying test, which could indicate a potential anti-obsessive effect, although the development of tolerance could be an important drawback.

  • Effects of fish oil on the central nervous system: A new potential antidepressant?
    K. Naliwaiko, R.L.F. Araújo, R.V. da Fonseca, J.C. Castilho, R. Andreatini, M.I. Bellissimo, B.H. Oliveira, E.F. Martins, R. Curi, L.C. Fernandes, and A.C. Ferraz

    Nutritional Neuroscience, ISSN: 1028415X, Pages: 91-99, Published: April 2004 Informa UK Limited
    In the last 100 years major depression has increased worldwide. In this study we provided coconut fat (CF, rich in saturated fatty acids) or fish oil (FO, rich in n-3 polyunsaturated fatty acids) to female rats throughout pregnancy and lactation and then to their offspring post-weaning and examined lipid brain profile and the possible effect of FO as antidepressant agent in the offspring in adulthood (F1). Rats were submitted to forced swimming test, elevated plus maze, Morris water maze and open field. Peroxidation rate in the cerebral cortex and hippocampus were measured. Docosahexaenoic acid (DHA) concentration in dam's milk, eicosapentaenoic acid (EPA) and DHA concentration in hippocampus and cerebral cortex from F1 rats FO supplemented increased significantly when compared to control (C) and CF rats. Arachidonic acid/EPA ratio in the cerebral cortex and hippocampus decreased in rats submitted to forced swimming test. Peroxidation rate were not different between the groups. Immobility time in the forced swimming test in FO group was reduced (p < 0.01) when compared to C and CF rats. We conclude that lifelong intake of FO was able to induce an antidepressant effect with EPA and DHA concentration increased in the cerebral cortex and hippocampus.

  • Behavioural and neurochemical effects of phosphatidylserine in MPTP lesion of the substantia nigra of rats
    Juliana Cini Perry, Claudio Da Cunha, Janete Anselmo-Franci, Roberto Andreatini, Edmar Miyoshi, Sergio Tufik, and Maria A.B.F. Vital

    European Journal of Pharmacology, ISSN: 00142999, Volume: 484, Issue: 2-3, Pages: 225-233, Published: 26 January 2004 Elsevier BV
    The present study investigated the effects of intranigral MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) infusion on rats treated with phosphatidylserine and evaluated in two memory tasks and on striatal dopamine levels. The results indicated that MPTP produced a significant decrease in the avoidance number in comparison to sham-operated and non-operated rats submitted to a two-way avoidance task. MPTP-lesioned rats exhibited an increase in the latencies to find the platform in cued version of the water maze in comparison to sham-operated and non-operated animals. The tested toxin reduced striatal dopamine levels in comparison to sham-operated and non-operated groups. A final surprising result was that phosphatidylserine was unable to reverse the cognitive deficits produced by MPTP or the reduction of striatal dopamine levels. In conclusion, the data suggest that MPTP is a good model to study the early impairment associated with Parkinson's disease and phosphatidylserine did not improve the memory impairment induced by MPTP.

  • Evaluation of the medical orientation for the benzodiazepine side effects
    Luciana Auchewski, Roberto Andreatini, José Carlos F Galduróz, and Roseli Boerngen de Lacerda

    Revista Brasileira de Psiquiatria, ISSN: 15164446, Pages: 24-31, Published: March 2004 FapUNIFESP (SciELO)
    OBJETIVOS: Os benzodiazepínicos, pelos seus empregos como ansiolítico, hipnótico, miorrelaxante e anticonvulsivante, são muito prescritos. Os efeitos colaterais que comprometem o paciente são: diminuição da atividade psicomotora, interação com outras drogas, como o álcool, e o desenvolvimento de dependência. Neste estudo, avaliou-se a qualidade da orientação médica sobre esses efeitos colaterais. MÉTODOS: Foram entrevistados 120 pacientes (39 homens e 81 mulheres) com idade média de 48 anos que procuraram as farmácias de Curitiba, Paraná, para comprar benzodiazepínicos. Para avaliar as orientações médicas recebidas sobre os efeitos colaterais dos medicamentos, aplicou-se um questionário com perguntas abertas e estimuladas. RESULTADOS: Treze por cento dos pacientes relataram ter sido orientados sobre os três tipos principais de efeitos colaterais, 27% a respeito de pelo menos dois e 40% sobre pelo menos um, enquanto que 19% não recebeu nenhuma orientação. A qualidade da orientação não foi influenciada pelo grau de instrução do paciente, pela especialidade do médico prescritor e pelo tipo de atendimento (particular ou público). Houve predomínio da orientação ''não beber'' (85%), seguida do cuidado para operar máquinas e dirigir veículos (46%), e por último, a orientação sobre o desenvolvimento de dependência (31%). CONCLUSÃO: Os resultados sugerem que os médicos estavam mais preocupados com o risco de interação com o álcool, que pode ser fatal. O elevado número de pacientes que usavam a medicação de modo contínuo por mais de um ano (61%), o insucesso na interrupção da medicação (94%) e a pouca orientação sobre o tempo de uso do medicamento (22%) podem indicar a falta de preocupação do médico com a possível dependência induzida pelos benzodiazepínicos.

  • Effects of Hypericum perforatum and paroxetine on rat performance in the elevated T-maze
    Venessa Beijamini and Roberto Andreatini

    Pharmacological Research, ISSN: 10436618, Pages: 199-207, Published: 1 August 2003 Elsevier BV
    Hypericum perforatum extract exhibits an antidepressant effect and since several antidepressant drugs are also effective on generalised anxiety disorder (GAD) and panic disorders (PD), H. perforatum may possess some anxiolytic/antipanic effect. Thus, the aim of the present study was to evaluate the putative antipanic/anxiolytic effect of standardised H. perforatum extract (LI 160) on rats tested in the elevated T-maze, an animal model of innate (panic) and learned (generalised) anxiety, at doses that exhibit antidepressant-like activity. H. perforatum (150, 300 and 500 mg/kg, administered orally 24, 18 and 1h before the test) decreased the immobility time in the forced swim test. Rats were treated orally with H. perforatum (150 or 300 mg/kg) or paroxetine (5mg/kg) 24, 18, and 1h before being tested in the elevated T-maze (subacute treatment). Immediately after this test, the animals were submitted to the open field to evaluate locomotor activity. Paroxetine was used as a positive control, since it was clinically effective in GAD and PD. Other groups of animals were submitted to the same drug treatment for 7 days (subchronic treatment). Paroxetine (5mg/kg) impaired inhibitory avoidance after subacute treatment, while subchronic administration increased one-way escape latency. Subacute treatment with H. perforatum (300 mg/kg) exerts a partial anxiolytic-like effect in the inhibitory avoidance task. Repeated administration of H. perforatum (300 mg/kg) induced an anxiolytic effect (decreased inhibitory avoidance) and an antipanic effect (increased one-way escape). No effect on locomotor activity was found with any treatment. Thus, the results suggest that H. perforatum extract could exert an anxiolytic and antipanic effect.

  • Reliability and clinical utility of a Portuguese version of the Abnormal Involuntary Movements Scale (AIMS) for tardive dyskinesia in Brazilian patients
    H. Tonelli, D. Tonelli, G.R. Poiani, M.A.B.F. Vital, and R. Andreatini

    Brazilian Journal of Medical and Biological Research, ISSN: 0100879X, Pages: 511-514, Published: 1 April 2003 FapUNIFESP (SciELO)
    The objective of the present study was to evaluate the reliability and clinical utility of a Portuguese version of the Abnormal Involuntary Movements Scale (AIMS). Videotaped interviews with 16 psychiatric inpatients treated with antipsychotic drugs for at least 5 years were evaluated. Reliability was assessed by the intraclass correlation coefficient (ICC) between three raters, two with and one without clinical training in psychopathology. Clinical utility was assessed by the difference between the scores of patients with (N = 11) and without (N = 5) tardive dyskinesia (TD). Patients with TD exhibited a higher severity of global evaluation by the AIMS (sum of scores: 4.2 +/- 0.9 vs 0.4 +/- 0.2; score on item 8: 2.3 +/- 0.3 vs 0.4 +/- 0.2, TD vs controls). The ICC for the global evaluation was fair between the two skilled raters (0.58-0.62) and poor between these raters and the rater without clinical experience (0.05-0.29). Thus, we concluded that the Portuguese version of the AIMS shows an acceptable inter-rater reliability, but only between clinically skilled raters, and that it is clinically useful.

  • Effects of Hypericum perforatum and paroxetine in the mouse defense test battery
    Vanessa Beijamini and Roberto Andreatini

    Pharmacology Biochemistry and Behavior, ISSN: 00913057, Pages: 1015-1024, Published: March 2003 Elsevier BV
    Since (a) Hypericum perforatum shows anxiolytic-like effect in some animal models, (b) antidepressant drugs (AD) have been used as the main drug treatment for panic disorder (PD), (c) AD are also effective in generalized anxiety disorder (GAD), and (d) H. perforatum exhibits antidepressant activity, it was hypothesized that H. perforatum might possess an antipanic-like and/or anxiolytic-like effect. Previous studies with the mouse defense test battery (MDTB) have suggested that this model may be useful for the investigation of anxiolytic-like and antipanic-like compounds. Thus, the aim of the present study was to evaluate the effect of H. perforatum extract in the MDTB. The effect of acute, subchronic (7 days), and chronic (21 days) H. perforatum (150 and 300 mg/kg) extract administration was evaluated in mice submitted to the MDTB. Paroxetine (5 mg/kg), a selective serotonin re-uptake inhibitor with anxiolytic and antipanic effect, was used as a positive control. The results showed that 21 days of repeated administration of H. perforatum 300 mg/kg and paroxetine 5 mg/kg reduced flight reactions (number of avoidances, avoidance distance, and overall flight speed) to the presence of the predator. While the effect of paroxetine confirms that MDTB is useful for the detection of antipanic-like drugs, the effect of H. perforatum suggests a putative antipanic-like effect for this extract. Moreover, after 21 days of repeated administration, paroxetine increased the number of approaches/withdrawals and reduced the number of upright postures, suggesting a partial anxiolytic-like effect, while H. perforatum only reduced the number of upright postures. The present results suggest anxiolytic-like and antipanic-like effects of H. perforatum extract. However, it should be emphasized that the risk assessment (the main index of anxiety) was not affected by the extract, while the attack reactions were only weakly modified.

  • Effect of valepotriates (valerian extract) in generalized anxiety disorder: A randomized placebo-controlled pilot study
    Roberto Andreatini, V�nia A. Sartori, Maria L. V. Seabra, and Jos� Roberto Leite

    Phytotherapy Research, ISSN: 0951418X, Pages: 650-654, Published: November 2002 Wiley
    The aim of the present study was to carry out a controlled pilot study on the putative anxiolytic effect of valepotriates. Thirty-six outpatients with generalized anxiety disorder (DSM III-R), after a 2-week wash-out, were randomized to one of the following three treatments for 4 weeks (n = 12 per group): valepotriates (mean daily dose: 81.3 mg), diazepam (mean daily dose: 6.5 mg), or placebo. A parallel, double-blind, flexible-dose, placebo-controlled design was employed. No significant difference was observed among the three groups at baseline or in the change from baseline on the Hamilton anxiety scale (HAM-A) or in the trait part of the state-trait anxiety inventory (STAI-trait). Moreover, the three groups presented a significant reduction in the total HAM-A scores. On the other hand, only the diazepam and valepotriates groups showed a significant reduction in the psychic factor of HAM-A. The diazepam group also presented a significant reduction of the STAI-trait. Although the principal analysis (HAM-A between group comparison) found negative results (probably due to the small sample size in each group), the preliminary data obtained in the present study suggest that the valepotriates may have a potential anxiolytic effect on the psychic symptoms of anxiety. However, since the number of subjects per group was very small, the present results must be viewed as preliminary. Thus, further studies addressing this issue are warranted.

  • Evaluation of the face validity of reserpine administration as an animal model of depression-Parkinson's disease association
    L Skalisz

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 879-883, Published: June 2002 Elsevier BV
    The aim of the present study was to develop an animal model for the study of depressive symptoms associated with Parkinson's disease (PD). Mice treated intraperitoneally with reserpine (RES), 2.0 and 1.0 mg/kg, or its vehicle (VEHIC) were submitted to the sucrose solution (2%) consumption test (a model employed to mimic the depressive symptoms found in PD) and to the spontaneous locomotor activity test (a model employed to mimic the motor impairment found in PD). All animals were submitted to both tests. Twenty-four hours after treatment, only RES 2.0-treated animals showed a significantly decreased preference for the sucrose solution (mean +/- S.E.M. RES 2.0 = 54.4 +/- 4.1%, RES 1.0 = 68.5 +/- 2.5%, VEHIC = 62.3 +/- 4.1%). There was no significant difference among groups in water, sucrose or total fluid consumption. Locomotor activity was significantly decreased by both RES doses (number of beam interruptions: RES 2.0 = 59.9 +/- 11.4, RES 1.0 = 82.2 +/- 9.7, VEHIC = 116.8 +/- 8.2). Thus, RES 2.0 administration to mice induced depressive (anhedonia) and motor (decreased locomotor activity) symptoms of depression-PD association. This suggests that the RES model shows an important aspect of face validity for the depressive state associated with PD, i.e., phenomenological similarities between the model and the situation being modeled.

  • The brain decade in debate: V-Neurobiology of depression
    Helena M.T. Barros, Helena M. Calil, Francisco S. Guimarães, Jair C. Soares, and Roberto Andreatini

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 613-617, Published: 2002 Elsevier BV
    Abstract This paper is a transcription of a virtual symposium on the neurobiology of depression, which was organized by the Brazilian Society for Neuroscience and Behavior (SBNeC). There is a consensus that the monoaminergic theory is still valid, but its initial formulation suffered several modifications to explain more recent findings. Moreover, it is naive to suppose that depression has only one substratum and probably various neurotransmitter systems should be involved. Although nowadays the focus is mainly put on the serotonin (5-HT) system, there are several evidences suggesting an important role for other systems. It is expected that neuroimaging research with more specific tracers will give important information on this subject. The hormonal modulation is another important aspect of this picture, particularly in relation to the gender differences observed in depression. The neurobiological relationship between mania and depression states is also discussed. The intracellular transduction mechanisms are a growing field in depression research, representing the central focus of the “molecular theory” of depression, and it is indicated as the most fruitful theory to the development of really new drugs to treat depression.

  • Behavioral effects of MK-801 on reserpine-treated mice
    Renata C Dutra, Ana Paula Andreazza, Roberto Andreatini, Sergio Tufik, and Maria A.B.F Vital

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 487-495, Published: 2002 Elsevier BV
    The effects of dizocilpine (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, were studied on dopamine-related behaviors induced by reserpine treatments. This study focuses on behavioral syndromes that may used as models for Parkinson's disease, or tardive dyskinesia, and its response after glutamatergic blockage. Reserpine (1 mg/kg), administered once every other day for 4 days, produced increases in orofacial dyskinesia, tongue protrusion and vacuous chewing in mice, which are signs indicative of tardive dyskinesia. Reserpine also produced tremor and catalepsy, which are signs suggestive of Parkinson's disease. MK-801 (0.1 mg/kg), administered 30 min before the observation test, prevented the vacuous chewing movements, tongue protrusions and catalepsy induced by reserpine. However, MK-801 injection produced a significant increase of tremor in reserpine-treated mice. Reserpine (1 mg/kg), administered 90 min before the test and followed by apomophine injection (0.1 mg/kg) 5 min before the test, did not produce oral dyskinesia in mice. On the other hand, reserpine induced increases in tremor and catalepsy compared to control mice. MK-801 (0.1 mg/kg) administration attenuated the catalepsy and tremor induced by reserpine. Pretreatment with reserpine (1 mg/kg) 24 h before the observation test produced increases in vacuous chewing movements and tongue protrusion, as well as increases in tremor and catalepsy, whereas MK-801 (0.1 mg/kg) injection 90 min before the test reversed the effects of reserpine. These results show that reserpine produces different and abnormal movements, which are related to dose and schedule employed and can be considered as parkinsonian-like and tardive dsykinesia signs. The glutamatergic blockage produced by NMDA can restore these signs, such as vacuous chewing movements, tongue protrusions, catalepsy and tremor according to the employed model.

  • The ethics of the use of placebo in clinical studies
    Jornal Brasileiro de Psiquiatria, ISSN: 00472085, Issue: 7-8, Pages: 241-245, Published: 2001

  • Memory disruption in rats with nigral lesions induced by MPTP: A model for early Parkinson's disease amnesia
    C Da Cunha

    Behavioural Brain Research, ISSN: 01664328, Volume: 124, Pages: 9-18, Published: 2001 Elsevier BV
    Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) caused a lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. The animals were then tested in the two-way active avoidance task. MPTP-treated animals presented lower learning scores in the training and test sessions, an effect that was not caused by motor impairment or by a decreased sensitivity to footshock since their reaction time to the footshock (unconditioned stimulus - UCS) was not reduced. These lower scores were also not attributable to lower acoustic sensitivity or to a slowing in the association of the sound cue (conditioned stimulus - CS) with the UCS since the reaction time to the CS in the active avoidance response did not differ between MPTP-treated and control groups. Therefore, these results are more properly attributable to an impairment of the memory acquisition and retention processes. In addition, this study is presented as a model of early Parkinson's Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes.

  • Pharmacological treatment of generalized anxiety disorder: Future perspectives
    Roberto Andreatini, Roseli Boerngen-Lacerda, and Dirceu Zorzetto Filho

    Revista Brasileira de Psiquiatria, ISSN: 15164446, Pages: 233-242, Published: 2001 FapUNIFESP (SciELO)
    O presente artigo apresenta uma visão atualizada e ampla do tratamento farmacológico do transtorno de ansiedade generalizada (TAG). São revistos os medicamentos com eficácia comprovada em estudos controlados e atualmente disponíveis na clínica (benzodiazepínicos, buspirona, antidepressivos, betabloqueadores, antipsicóticos e extrato de kava-kava). A seguir, baseados nesses dados, propõe-se um algoritmo de tratamento do TAG. São apresentadas as principais linhas de pesquisa de novos fármacos ansiolíticos, descrevendo os principais achados clínicos e pré-clínicos.

  • The brain decade in debate: II. Panic or anxiety? From animal models to a neurobiological basis
    R. Andreatini, C. Blanchard, R. Blanchard, M.L. Brandão, A.P. Carobrez, G. Griebel, F.S. Guimarães, S.L. Handley, F. Jenck, J.R. Leite, J. Rodgers, L.C. Schenberg, C. Da Cunha, and F.G. Graeff

    Brazilian Journal of Medical and Biological Research, ISSN: 0100879X, Pages: 145-154, Published: February 2001 FapUNIFESP (SciELO)
    This article is a transcription of an electronic symposium sponsored by the Brazilian Society of Neuroscience and Behavior (SBNeC). Invited researchers from the European Union, North America and Brazil discussed two issues on anxiety, namely whether panic is a very intense anxiety or something else, and what aspects of clinical anxiety are reproduced by animal models. Concerning the first issue, most participants agreed that generalized anxiety and panic disorder are different on the basis of clinical manifestations, drug response and animal models. Also, underlying brain structures, neurotransmitter modulation and hormonal changes seem to involve important differences. It is also common knowledge that existing animal models generate different types of fear/anxiety. A challenge for future research is to establish a good correlation between animal models and nosological classification.

  • 5-HT 3 antagonists: A new class of anxiolytic drugs? The example of ondansetron
    Revista de Psiquiatria Clinica, ISSN: 01016083, Pages: 272-279, Published: 2000

  • Phosphatidylserine reverses reserpine-induced amnesia
    Célia S.D Alves, Roberto Andreatini, Cláudio da Cunha, Sérgio Tufik, and Maria A.B.F Vital

    European Journal of Pharmacology, ISSN: 00142999, Volume: 404, Issue: 1-2, Pages: 161-167, Published: 15 September 2000 Elsevier BV
    The effects of phosphatidylserine (PS) were studied in rats treated with reserpine (1 mg/kg) immediately after training in the passive avoidance task. In experiment I, phosphatidylserine (25 mg/kg) was administered 30 min before or immediately after training. Acute pre- or post-treatment with phosphatidylserine was effective in reversing the amnestic effect of reserpine in test trials performed 24 h and 1 week after training. Experiment II was performed to determine if the long-term pretreatment with phosphatidylserine (25 mg/kg) for 7 days is able to protect the rats against the amnestic effects of reserpine in this task. The data show that phosphatidylserine reverses the impairment induced by reserpine in trials performed 24 h and 1 week after training. These results indicate that the memory deficits associated with catecholamine depletion caused by reserpine can be attenuated by acute pre- or post-training or by long-term pretreatment with this phospholipid.

  • Animal models: Trait or state measure? The test-retest reliability of the elevated plus-maze and behavioral despair
    Roberto Andreatini and Leila F.S. Bacellar

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 549-560, Published: May 2000 Elsevier BV
    1. The use of animal models in certain types of psychobiological studies (for instance, the relationship between anxiety and depression) requires that the behavior measured is stable over time. 2. The test-retest reliability of the elevated plus-maze indexes of anxiety and the immobility time in the behavioral despair were evaluated. 3. The behavior of two groups of drug naive mice was measured on two occasions on the same test, 1 week apart, on the elevated plus-maze or on the behavioral despair and then the intraclass correlation coefficient and kappa were calculated. 4. These behaviors showed a very low intraclass correlation coefficient (0.02 - 0.05) and low kappa (-0.08 - 0.21) in the test-retest design, which suggest a poor reliability of these measures. 5. These results suggest that the behavioral parameters of the elevated plus-maze and the behavioral despair are not stable and therefore they are possibly more related to state than trait characteristics. Therefore they appear to be not appropriate to evaluate trait characteristics which are supposed to be stable over time without treatment.

  • The antidepressive-like effect of oxcarbazepine: Possible role of dopaminergic neurotransmission
    Samia R.L Joca, Luana L Skalisz, Vanessa Beijamini, Maria Aparecida B.F Vital, and Roberto Andreatini

    European Neuropsychopharmacology, ISSN: 0924977X, Pages: 223-228, Published: 2000 Elsevier BV
    It has been previously shown that oxcarbazepine (OXCBZ), a keto-analogue of carbamazepine, exhibits an antidepressive-like effect profile in the learned helplessness and forced swimming test (FST). Since carbamazepine possesses dopaminergic effect, the present study was carried out to evaluate the extent to which the antidepressive effect of OXCBZ might be mediated by dopaminergic system. Thus, the effects of OXCBZ in haloperidol-induced catalepsy and apomorphine-induced stereotypy were studied. The anti-immobility effect of OXCBZ in the FST was also evaluated in haloperidol pre-treated rats. OXCBZ (40 and 80 mg/kg, i.p.) dose-dependently reduced the catalepsy induced by haloperidol (2.0 mg/kg, i.p.). Moreover, OXCBZ (80 mg/kg, but not 20 or 40 mg/kg, i.p.) increased the intensity of apomorphine-induced stereotypy (0.6 mg/kg, s.c.). Finally, it was observed that the combination of OXCBZ (80 mg/kg, i. p.) and haloperidol (0.5 mg/kg, i.p.) antagonized the anti-immobility effect of OXCBZ and further increased the immobility time when compared to haloperidol alone. Haloperidol alone (0.5 or 1. 0 mg/kg) did not change the immobility time. Thus, these results suggest that OXCBZ could enhance dopaminergic neurotransmission, which might mediate its antidepressive-like effect.

  • Effects of moderate altitude on motor skills in elite figure roller skaters
    Journal of Sports Sciences, ISSN: 02640414, Pages: 560, Published: 2000

  • The video-recorded Stroop Color-Word Test as a new model of experimentally-induced anxiety
    JoséRoberto Leite, Maria De Lourdes V. Seabra, Vania A. Sartori, and Roberto Andreatini

    Progress in Neuro-Psychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 809-822, Published: July 1999 Elsevier BV
    1. The use of the Stroop Color-Word Test as a model of experimentally induced anxiety was evaluated. 2. First, the authors examined the influence of trait anxiety and the type of instructions on the anxiety state level. Subjects with high trait anxiety (above 50 on State-Trait Anxiety Scale--STAI) showed a significant increase in anxiety state only with limited time (2 minutes) and error signal (with a ringing bell) procedures. This increase was blocked by diazepam (DZP) 5.0 mg p.o. both on pre- and post-test measures, but it was not changed by placebo administration. 3. The public performance simulation (with a video-camera) was effective to raise the anxiety state on normal volunteers with mean trait anxiety (between 30 and 50 on STAI). This raise was prevented with diazepam 5.0 mg p.o. but it was not prevented with placebo administration. 4. As a whole, these data suggest that the Video-recorded Stroop Color-Word Test is an effective anxiety provoking test, able to detect the effect of standard anxiolytic drug and stressed the importance of trait anxiety level and the instructions on tests that induced anxiety experimentally.

  • The relationship between anxiety and depression in animal models: A study using the forced swimming test and elevated plus-maze
    R. Andreatini and L.F.S. Bacellar

    Brazilian Journal of Medical and Biological Research, ISSN: 0100879X, Pages: 1121-1126, Published: September 1999 FapUNIFESP (SciELO)
    The present study evaluated the correlation between the behavior of mice in the forced swimming test (FST) and in the elevated plus-maze (PM). The effect of the order of the experiments, i.e., the influence of the first test (FST or PM) on mouse behavior in the second test (PM or FST, respectively) was compared to handled animals (HAND). The execution of FST one week before the plus-maze (FST-PM, N = 10), in comparison to mice that were only handled (HAND-PM, N = 10) in week 1, decreased % open entries (HAND-PM: 33.6 +/- 2.9; FST-PM: 20.0 +/- 3.9; mean +/- SEM; P<0.02) and % open time (HAND-PM: 18.9 +/- 3.3; FST-PM: 9.0 +/- 1.9; P<0.03), suggesting an anxiogenic effect. No significant effect was seen in the number of closed arm entries (FST-PM: 9.5 (7.0-11.0); HAND-PM: 10.0 (4.0-14.5), median (interquartile range); U = 46.5; P>0.10). A prior test in the plus-maze (PM-FST) did not change % immobility time in the FST when compared to the HAND-FST group (HAND-FST: 57.7 +/- 3.9; PM-FST: 65.7 +/- 3.2; mean +/- SEM; P>0.10). Since these data suggest that there is an order effect, the correlation was evaluated separately with each test sequence: FST-PM (N = 20) and PM-FST (N = 18). There was no significant correlation between % immobility time in the FST and plus-maze indexes (% time and entries in open arms) in any test sequence (r: -0.07 to 0.18). These data suggest that mouse behavior in the elevated plus-maze is not related to behavior in the forced swimming test and that a forced swimming test before the plus-maze has an anxiogenic effect even after a one-week interval.

  • The 'anxiety state' and its relation with rat models of memory and habituation
    Rafaela L. Ribeiro, Roberto Andreatini, Claudia Wolfman, Haydeé Viola, Jorge H. Medina, and Claudio Da Cunha

    Neurobiology of Learning and Memory, ISSN: 10747427, Pages: 78-94, Published: September 1999 Elsevier BV
    Rats selected as "anxious", "nonanxious," or normal according to their behavior in an elevated plus maze were submitted to memory tasks and the densities of central benzodiazepine receptors in the amygdala and the hippocampus were studied. Anxious rats exibited better retention scores in the inhibitory avoidance task while nonanxious rats exibited worse retention scores in inhibitory and two-way active avoidance tasks compared to normal rats. No significant differences were detected in the retention scores for habituation to an open field. Nonanxious rats presented a lower benzodiazepine receptor density in the hippocampus but not in the amygdala compared to the other groups. These data suggest that the benzodiazepine receptors are involved in the effect of "anxiety" or emotional states on memory storage processes.

  • The effect of oxcarbazepine on behavioural despair and learned helplessness
    Vanessa Beijamini, Luana L Skalisz, Samia R.L Joca, and Roberto Andreatini

    European Journal of Pharmacology, ISSN: 00142999, Volume: 347, Pages: 23-27, Published: 17 April 1998 Elsevier BV
    The effect of oxcarbazepine was evaluated in two tests of depression (forced swimming and learned helplessness) and in the open-field test. Acute (three times over 24 h) oxcarbazepine 80 mg/kg (but not 40 mg/kg) decreased immobility time in the forced swimming test. In the learned helplessness test, 4 days of treatment with oxcarbazepine 80 mg/kg reversed the deficits induced by foot-shock in rats submitted to the two-way active avoidance test. Oxcarbazepine 80 mg/kg did not modify the behaviour of rats in the open-field test, an indication that, at this dose, oxcarbazepine did not show a locomotor stimulatory effect. Thus, the data of the present study suggest that oxcarbazepine has a potential antidepressive effect.

  • Prolonged treatment with carbamazepine increases the stimulatory effects of ethanol in mice
    Rosana Camarini, Roberto Andreatini, and Maristela Goldnadel Monteiro

    Alcohol, ISSN: 07418329, Pages: 305-308, Published: July 1995/August 1995 Elsevier BV
    Carbamazepine (CBZ) has been used in the treatment of alcohol withdrawal (AW). However, cases of induction of euphoric feelings when mixed with alcohol have been reported. We verified whether CBZ could potentiate ethanol stimulatory effects in animals. Two groups of mice were injected with saline (group I) or 2 g/kg ethanol (group II) IP, for 20 days. On the next day, each group was divided into two subgroups that received either a single dose of CBZ (10 mg/kg) or vehicle IP, followed, 30 min later, by saline or ethanol injection. Locomotor activity was measured. Acute CBZ did not change locomotor activity of ethanol-treated mice. Treatment with CBZ or vehicle continued for 6 days. Finally, on the 28th day, 30 min after the last CBZ or vehicle injection, an ethanol challenge was given to group II and a saline injection to group I. The results showed a significant potentiation of ethanol stimulatory effects by chronic CBZ treatment. Data indicated that CBZ should be cautiously administered to alcohol-dependent patients.

  • Effect of valepotriates on the behavior of rats in the elevated plus-maze during diazepam withdrawal
    Roberto Andreatini and JoséR. Leite

    European Journal of Pharmacology, ISSN: 00142999, Volume: 260, Issue: 2-3, Pages: 233-235, Published: 1 August 1994 Elsevier BV
    The effect of a mixture of valepotriates on the elevated plus-maze performance of diazepam withdrawn rats was evaluated. The rats were chronically (28 days) treated with diazepam (doses increased up to 5.0 mg/kg) and then treated with control solution for 3 days to induce a withdrawal syndrome. Chronically vehicle-treated rats were used as control. The abstinent animals treated with vehicle showed a significant decrease in the percentage of time spent in the open arms when compared with the control animals. Diazepam and valerian 12.0 mg/kg reversed this anxiogenic effect. Valerian 6.0 mg/kg did not show any difference in relation to the others group.

  • Panic attacks in a multiple sclerosis patient
    Roberto Andreatini, Vânia A. Sartori, JoséR. Leite, and Acary S.B. Oliveira

    Biological Psychiatry, ISSN: 00063223, Pages: 133-134, Published: 15 January 1994 Elsevier BV
    The purpose of this report is to present a case in which multiple sclerosis is associated with recurrent panic attacks and a depressive episode

  • Evidence against the involvement of ACTH/CRF release or corticosteroid receptors in the anxiolytic effect of corticosterone
    Brazilian Journal of Medical and Biological Research, ISSN: 0100879X, Pages: 1237-1241, Published: 1994

  • The effect of corticosterone in rats submitted to the elevated plus-maze and to to pentylenetetrazol-induced convulsions
    Roberto Andreatini and JoséR. Leite

    Progress in Neuropsychopharmacology and Biological Psychiatry, ISSN: 02785846, Pages: 1333-1347, Published: December 1994 Elsevier BV
    1. In order to examine the effects of corticosterone in the anxiety response, the effect of acute, subchronic and chronic corticosterone (CORT) administration were studied using two animal models to study anxiolytic effects of drugs: the elevated plus-maze and the blockade of pentylenetetrazol (PTZ)-induced clonic convulsion. 2. The results obtained with the plus-maze showed an increase in the percentage of open arm entries and time spent in the open arms after acute treatment with the CORT. These results may be interpreted as an anxiolytic effect of corticosterone. Three days of vehicle treatment followed by an acute CORT administration, produced results that should also indicate anxiolytic effect of the corticosteroid. No effect was seen after 14 days of vehicle treatment followed by an acute CORT injection. Subchronic or chronic CORT treatment did not produce results different from controls. CORT treatment did not affect the PTZ-induced clonic convulsion. 3. In conclusion these results suggest that the acute anxiolytic effect observed in the elevated plus-maze did not occur after repeated CORT administration or mild stressors. Moreover they also suggest that the anxiolytic effect did not involve GABA mechanisms.

  • Alcohol dependence criteria in DSM‐III‐R: presence of symptoms according to degree of severity

    Addiction, ISSN: 09652140, eISSN: 13600443, Pages: 1129-1134, Published: September 1994 Wiley
    According to DSM-III-R a positive diagnosis of alcohol dependence requires the presence of at least three of nine symptoms of a core dependence syndrome. In this study the presence of the nine symptoms according to degree of the severity of dependence is examined in 99 patients (mild, n = 23; moderate, n = 26; and severe, n = 50). It is shown that although the cut-off point for a positive diagnosis of dependence is the presence of "any three" out of nine DSM-III-R criteria, specific symptoms ("excessive drinking", "desire or efforts to control drinking", and "drinking despite major problems") have a high probability of occurrence across the dependence severity range (mild, moderate or severe). Conversely, other symptoms appear prominently only in the more severe cases ("much time devoted to alcohol", "important activities given up", and "drinking to relieve withdrawal"). The results suggest that in the DSM-III-R criteria for alcohol dependence some symptoms are more frequently associated with the diagnosis, while other symptoms are associated with severity of the alcohol dependence disorder.

  • Anxiolytic effect of carbamazepine in experimentally-induced anxiety
    Journal of Drug Development, ISSN: 09529500, Pages: 251-254, Published: 1993

  • Amnesic effects of benzodiazepines
    Revista da Associacao Brasileira de Psiquiatria, ISSN: 01027646, Pages: 51-58, Published: 1993

  • The pre-clinical evaluation of the Artemisia sp. toxicology
    Revista Brasileira de Farmacia, ISSN: 0370372X, Pages: 37-42, Published: 1992