Garcia-Fuster, M. J. | bioRxiv Science

bioRxiv2023

Evaluating the role of inhibiting the biosynthesis of estrogens in the sex-specific antidepressant-like effects of ketamine in rats

Ketamine has been recently approved to treat resistant depression; however preclinical studies showed sex differences in its efficacy. Sex steroids, such as estrogen and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. Therefore, the present study evaluated the role of inhibiting estrogen biosynthesis with letrozole, an aromatase inhibitor that catalyzes the conversion of androgen into estrogen, in the differential antidepressant-like-response induced by ketamine with sex. We performed several consecutive studies in adult Sprague-Dawley rats to evaluate potential sex differences in the antidepressant-like effects of ketamine (5 mg/kg, 7 days, i.p.), letrozole (1 mg/kg, 8 days, i.p.) and their combination (letrozole pre-treatment 3 h before ketamine). Acute and repeated antidepressant-like responses were ascertained in a series of behavioral tests (forced-swim, novelty-suppressed feeding, two-bottle choice for sucrose preference). The main results proved clear sex differences in the antidepressant-like response induced by ketamine, which was observed following a repeated paradigm in adult male rats, but rendered inefficacious in female rats. Moreover, decreasing estrogen production with letrozole induced on itself an antidepressant-like response in female rats, while also improved ketamines response in male rats (i.e., quicker response, only after a single dose). Interestingly, both the antidepressant-like effects induced by ketamine in male rats or letrozole in female rats persisted over time up to 65 days post-treatment, suggesting long-term sex-directed benefits for these drugs. The present results demonstrated a sex-specific role for inhibiting estrogen biosynthesis in the antidepressant-like response induced by ketamine in male rats. Moreover, letrozole presented itself as a potential antidepressant for females with persistent effects over time. Clearly, estrogen production is key in modulating, in a sex-specific manner, affective-like responses and thus deserve further studies.

pharmacology and toxicology↗

bioRxiv2022

Cocaine during adolescence differentially impacts psychomotor sensitization and epigenetic profiles in adult male rats with divergent affective phenotypes

While early life drug use reliably predicts addiction liability in adulthood, the molecular mechanism by which this occurs, and the degree genetic predisposition is involved is not known. We used a unique genetic rat model of temperament to determine the impact of adolescent cocaine experience on adult psychomotor sensitization and epigenetic profiles in the striatum. Relative to adult bred low-responder (bLR) rats, bred high-responders (bHR) are more sensitive to the psychomotor-activating effects of cocaine and reinstate drug-seeking behavior more readily following prolonged cocaine exposure and a period of abstinence. We found that a 7-day sensitizing cocaine regimen (15 mg/kg/day) during either adolescence or adulthood produced psychomotor sensitization in bHRs only, while a dual cocaine exposure prevents further sensitization, suggesting limits on neuroplasticity. By contrast, adolescent cocaine in bLRs shifted their resilient phenotype, rendering them more responsive to cocaine in adulthood when initially challenged with cocaine We then assessed two functionally opposite epigenetic chromatin modifications, previously implicated in addiction liability, permissive acetylation (ac) and repressive tri-methylation (me3), on histone 3 lysine 9 (H3K9) in four sub-regions of the striatum. In bHRs, decreased repressive histone, H3K9me3, and increased permissive histone, acH3K9, in nucleus accumbens core associated with cocaine sensitization. However, there were limits on these epigenetic changes that paralleled the behavioral limits on further sensitization. In bLRs, the combination of cocaine exposure in adolescence and adulthood, which lead to an increase in their responsiveness to a cocaine challenge, also increased acH3K9 expression in the core. Thus, adolescent cocaine experience interacts with genetic background to elicit different behavioral profiles relevant to addiction in adulthood, with concurrent modifications in the epigenetic histone profiles in the nucleus accumbens that associate with cocaine sensitization and with metaplasticity. SIGNIFICANCE STATEMENTAdolescence is a critical period when brain developmental trajectories continue to be established and when most illicit drug use is initiated in humans. Notably, however, only a minority of adolescent drug users go on to develop substance use disorders in adulthood. We hypothesize that individual differences in genetic vulnerability, temperamental phenotype and adolescent drug history intersect to modify life-long drug abuse liability, with epigenetic modification playing an important role in this interplay. We tested this hypothesis in a genetic animal model of temperament. Our results show that adolescent cocaine experience induces psychomotor sensitization in vulnerable individuals, and that a dual exposure to cocaine (both in adolescence and adulthood) limits further sensitization in these individuals, an example of metaplasticity. By contrast, individuals who are typically resilient become more responsive to cocaine when exposed to this drug during adolescence and are then re-exposed as adults. Differences in behavioral response to cocaine were associated with unique epigenetic changes in the nucleus accumbens core. These findings shed light on the interplay of genes, environment and adolescent exposure to drugs in susceptibility to substance use disorders.

neuroscience↗