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Adolescent drug use reliably predicts increased addiction liability in adulthood, but not all individuals are equally impacted. To explore the biological bases of this differential reactivity to early life drug experience, we used a genetic rat model of temperament and evaluated the impact of adolescent cocaine exposure on adult psychomotor sensitization. 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/or 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 prevented further sensitization, suggesting limits on neuroplasticity. By contrast, adolescent cocaine in bLRs shifted their resilient phenotype, rendering them more responsive to cocaine in adulthood following adolescent cocaine. To begin to explore the neural correlates of these behavioral phenotypes, we assessed two functionally opposite epigenetic chromatin modifications implicated in addiction liability, permissive acetylation (ac) and repressive tri-methylation (me3) on Histone 3 Lysine 9 (H3K9), in four striatal sub-regions. In bHRs, decreased H3K9me3 and increased acH3K9 in the nucleus accumbens (NAc) core associated with cocaine sensitization. In bLRs, the combination of cocaine exposure in adolescence and adulthood, which lead to an increased response to a cocaine challenge, also increased acH3K9 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 NAc that associate with cocaine sensitization and with metaplasticity.

Aging predisposes to late-life depression and since antidepressants are known to change their efficacy with age, novel treatment options are needed for our increased aged population. In this context, the goal of the present study was to evaluate the potential antidepressant-like effect of cannabidiol in aged rats. For this purpose, 19–21-month-old Sprague–Dawley rats were treated for 7 days with cannabidiol (dose range: 3–30 mg/kg) and scored under the stress of the forced-swim test. Hippocampal cannabinoid receptors and cell proliferation were evaluated as potential molecular markers underlying cannabidiol’s actions. The main results of the present study demonstrated that cannabidiol exerted a dose-dependent antidepressant-like effect in aged rats (U-shaped, effective at the intermediate dose of 10 mg/kg as compared to the other doses tested), without affecting body weight. None of the molecular markers analyzed in the hippocampus were altered by cannabidiol’s treatment. Overall, this study demonstrated a dose-dependent antidepressant-like response for cannabidiol at this age-window (aged rats up to 21 months old) and in line with other studies suggesting a beneficial role for this drug in age-related behavioral deficits.

The association of cocaine use disorder (CUD) and comorbid major depressive disorder (MDD; CUD/MDD) is characterized by high prevalence and poor treatment outcomes. CUD/MDD may be primary (primary MDD) or cocaine-induced (CUD-induced MDD). Specific biomarkers are needed to improve diagnoses and therapeutic approaches in this dual pathology. Platelet biomarkers [5-HT2A receptor and imidazoline receptor antisera selected (IRAS)/nischarin] were assessed by Western blot in subjects with CUD and primary MDD (n = 16) or CUD-induced MDD (n = 9; antidepressant free, AD-; antidepressant treated, AD+) and controls (n = 10) at basal level and/or after acute tryptophan depletion (ATD). Basal platelet 5-HT2A receptor (monomer) was reduced in comorbid CUD/MDD subjects (all patients: 43%) compared to healthy controls, and this down-regulation was independent of AD medication (decreases in AD-: 47%, and in AD+: 40%). No basal differences were found for IRAS/nischarin contents in AD+ and AD-comorbid CUD/MDD subjects. The comparison of IRAS/nischarin in the different subject groups during/after ATD showed opposite modulations (i.e., increases and decreases) in response to low plasma tryptophan levels with significant differences discriminating between the subgroups of CUD with primary MDD and CUD-induced MDD. These specific alterations suggested that platelet IRAS/nischarin might be useful as a biomarker to discriminate between primary and CUD-induced MDD in this dual pathology., The study was supported by grants SAF2011-29918 (JAG-S) and SAF2014-55903-R (MJG-F) from Ministerio de Economia y Competitividad (MINECO) and Fondo Europeo de Desarrollo Regional (FEDER) and by grants PS09/02121 and PI12/01838 (MT) from Instituto de Salud Carlos III (ISCIII) and FIS-FEDER, Madrid, Spain. The research was also funded by Redes Tematicas de Investigacion Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA, RD12/0028/0011, RD12/0028/0009, RD16/0017/0003, and RD16/0017/0010) (ISCIII and FEDER), Madrid, Spain. This work was also supported by grants 2012/011 and 2016/002 (MJG-F) from Delegacion del Gobierno para el Plan Nacional sobre Drogas, Ministerio de Sanidad, Servicios Sociales e Igualdad, Madrid, Spain. BK was supported by a predoctoral contract from RETICS-RTA. MJG-F is a Ramon y Cajal Researcher (MINECO-UIB). JG-S is a member of the Institut d'Estudis Catalans (Barcelona, Catalonia, Spain). We are grateful to Esther Menoyo, Marta Perez, Soraya Martin, and Clara Gibert for their valuable assistance throughout the clinical part of the study.