Physiology, Neuroscience, Pharmacology, Toxicology and Pharmaceutics, Neuropsychology and Physiological Psychology
13
Scopus Publications
Scopus Publications
Evaluating the daily modulation of FADD and related molecular markers in different brain regions in male rats Fernando Yáñez‐Gómez, Laura Gálvez‐Melero, Sandra Ledesma‐Corvi, Cristian Bis‐Humbert, Elena Hernández‐Hernández, et al. Journal of Neuroscience Research, 2024 Fas‐Associated protein with Death Domain (FADD), a key molecule controlling cell fate by balancing apoptotic versus non‐apoptotic functions, is dysregulated in post‐mortem brains of subjects with psychopathologies, in animal models capturing certain aspects of these disorders, and by several pharmacological agents. Since persistent disruptions in normal functioning of daily rhythms are linked with these conditions, oscillations over time of key biomarkers, such as FADD, could play a crucial role in balancing the clinical outcome. Therefore, we characterized the 24‐h regulation of FADD (and linked molecular partners: p‐ERK/t‐ERK ratio, Cdk‐5, p35/p25, cell proliferation) in key brain regions for FADD regulation (prefrontal cortex, striatum, hippocampus). Samples were collected during Zeitgeber time (ZT) 2, ZT5, ZT8, ZT11, ZT14, ZT17, ZT20, and ZT23 (ZT0, lights‐on or inactive period; ZT12, lights‐off or active period). FADD showed similar daily fluctuations in all regions analyzed, with higher values during lights off, and opposite to p‐ERK/t‐ERK ratios regulation. Both Cdk‐5 and p35 remained stable and did not change across ZT. However, p25 increased during lights off, but exclusively in striatum. Finally, no 24‐h modulation was observed for hippocampal cell proliferation, although higher values were present during lights off. These results demonstrated a clear daily modulation of FADD in several key brain regions, with a more prominent regulation during the active time of rats, and suggested a key role for FADD, and molecular partners, in the normal physiological functioning of the brain's daily rhythmicity, which if disrupted might participate in the development of certain pathologies.
Cannabidiol or ketamine for preventing the impact of adolescent early drug initiation on voluntary ethanol consumption in adulthood Carles Colom-Rocha, Cristian Bis-Humbert, M. Julia García-Fuster Frontiers in Pharmacology, 2024 BackgroundFew studies have previously evaluated the long-term impact of initiating the combined use of alcohol and cocaine early-in-life during adolescence. Our preclinical study characterized changes in affective-like behavior and/or voluntary ethanol consumption emerging later on in adulthood induced by a prior adolescent drug exposure, as well as tested therapeutical interventions (i.e., cannabidiol or ketamine) to prevent the observed effects.MethodsWe performed three independent studies with male and female Sprague-Dawley rats, treated in adolescence (postnatal days, PND 29–38) with non-contingent paradigms of ethanol, cocaine, their combination or vehicle. Later on, adult rats were (1) scored for their affective-like state (forced-swim, elevated-plus maze, novelty-suppressed feeding, sucrose preference), (2) allowed to freely drink ethanol for 6 weeks (two-bottle choice), or (3) treated with cannabidiol or ketamine before given access to ethanol in adulthood.ResultsNo signs of increased negative affect were observed in adulthood following the adolescent treatments. However, adolescent ethanol exposure was a risk-factor for later developing an increased voluntary ethanol consumption in adulthood, both for male and female rats. This risk was similar when ethanol was combined with adolescent cocaine exposure, since cocaine alone showed no effects on later ethanol intake. Finally, rats exposed to adolescent ethanol and pretreated in adulthood with cannabidiol (and/or ketamine, but just for females) reduced their ethanol voluntary consumption.ConclusionOur data provided two therapeutical options capable of preventing the impact of an early drug initiation during adolescence by decreasing voluntary ethanol consumption in adult rats
Evaluating signs of hippocampal neurotoxicity induced by a revisited paradigm of voluntary ethanol consumption in adult male and female Sprague-Dawley rats Carles Colom-Rocha, Cristian Bis-Humbert, M. Julia García-Fuster Pharmacological Reports, 2023 Background Binge alcohol drinking is considered a prominent risk factor for the development of alcohol-use disorders, and could be model in rodents through the standard two-bottle preference choice test. The goal was to recreate an intermittent use of alcohol during 3 consecutive days each week to ascertain its potential impact on hippocampal neurotoxicity (neurogenesis and other neuroplasticity markers), and including sex as a biological variable, given the well-known sex differences in alcohol consumption. Methods Ethanol access was granted to adult Sprague–Dawley rats for 3 consecutive days per week, followed by 4 days of withdrawal, during 6 weeks, mimicking the most common pattern of intake in people, drinking over the weekends in an intensive manner. Hippocampal samples were collected to evaluate signs of neurotoxicity. Results Female rats consumed significantly more ethanol than males, although intake did not escalate over time. Ethanol preference levels remained below 40% over time and did not differ between sexes. Moderate signs of ethanol neurotoxicity were observed in hippocampus at the level of decreased neuronal progenitors (NeuroD + cells), and these effects were independent of sex. No other signs of neurotoxicity were induced by ethanol voluntary consumption when measured through several key cell fate markers (i.e., FADD, Cyt c, Cdk5, NF-L) by western blot analysis. Conclusions Overall, the present results suggest that even though we modeled a situation where no escalation in ethanol intake occurred across time, mild signs of neurotoxicity emerged, suggesting that even the use of ethanol during adulthood in a recreational way could lead to certain brain harm.
Adolescent cocaine induced persistent negative affect in female rats exposed to early-life stress Cristian Bis-Humbert, M. Julia García-Fuster Psychopharmacology, 2021 Rationale The combination of several risk factors (sex, a prior underlying psychiatric condition, or early drug initiation) could induce the emergence of negative affect during cocaine abstinence and increase the risk of developing addiction. However, most prior preclinical studies have been centered in male rodents, traditionally excluding females from these analyses. Objectives To ascertain the behavioral and neurochemical consequences of adolescent cocaine exposure when the combination of several risk factors is present (female, early-life stress). Methods Whole litters of Sprague–Dawley rats were exposed to maternal deprivation for 24 h on postnatal day (PND) 9. Cocaine was administered in adolescence (15 mg/kg/day, i.p., PND 33–39). Negative affect was assessed by several behavioral tests (forced swim, open field, novelty-suppressed feeding, sucrose preference). Hippocampal cell fate markers were evaluated by western blot (FADD, Bax, cytochrome c) or immunohistochemistry (Ki-67; cell proliferation). Results Maternal deprivation is a suitable model of psychiatric vulnerability in which to study the impact of adolescent cocaine in female rats. While adolescent cocaine did not alter affective-like behavior during adolescence, a pro-depressive–like state emerged during adulthood, exclusively in rats re-exposed to cocaine during abstinence. FADD regulation by cocaine in early-life stressed female rats might contribute to certain hippocampal neuroadaptations with some significance to the observed induced negative affect. Conclusions Adolescent cocaine induced persistent negative affect in female rats exposed to early-life stress, highlighting the risk of early drug initiation during adolescence for the emergence of negative reinforcement during abstinence likely driving cocaine addiction vulnerability, also in female rats.
