Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereasDnmt3aknock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out ofDnmt3awas a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability.SIGNIFICANCE STATEMENTWomen have a higher incidence of depression than men. However, preclinical models, the first step in developing new diagnostics and therapeutics, have been performed mainly on male subjects. Using a stress-based animal model of depression that causes behavioral effects in females but not males, we demonstrate a sex-specific transcriptional profile in brain reward circuitry. This transcriptional profile can be altered by removal of an epigenetic mechanism, which normally suppresses DNA transcription, creating a hybrid male/female transcriptional pattern. Removal of this epigenetic mechanism also induces behavioral resilience to stress in females. These findings shed new light onto molecular factors controlling sex differences in stress response.

Background: Chronic cocaine consumption is associated to a decrease in mesolimbic dopamine transmission that maintains drug intake. Transcranial Magnetic Stimulation (TMS) is gaining reliability a useful therapeutic tool in drug addiction since it can modulate cortico-limbic activity resulting in reduction of drug craving. Aims: In the present study we investigated the therapeutic effect of bilateral TMS of prefrontal cortex (PFC) in reducing cocaine intake, in a sample of treatment-seeking patients with current cocaine use disorder (DSM-V). Methods: 10 cocaine addicts (DSM-V) were randomly assigned to the active or sham stimulation protocol in a double-blind experimental design. Twelve repetitive TMS (rTMS) sessions were administered 3 times a week for 4 weeks at 100% of motor threshold, over bilateral PFC. Cocaine intake (ng/mg) was assessed by hair analysis at baseline (before treatment, T0), after one month (end of treatment, T1), 3 (T2) and 6 (T3) months later. All subjects received psychological support weekly. Results: The two-way ANOVA for repeated measures did not show a significant effect of the interaction between time and treatment (F4,32= 0.35; p=.87). Despite that result indicated no difference in the effect of the two conditions (active vs sham) along time, a decreasing trend in cocaine consumption in active TMS group (F3,23=3.42; p=.04) vs sham (F3,15=1.88; p=.20) was observed when we performed exploratory analysis with time as factor . Indeed, Post-hoc comparisons showed a significant reduction in the amount of cocaine detected from the onset to three months later (T0-T2; p=.02) and to the end of treatment (T0-T3; p=.01) in addicts from the active group. Conclusions: Bilateral rTMS of PFC at 10 Hz did not show a significant effect on cocaine intake compared to sham. However, a long-term reduction in cocaine intake in active TMS treated patients was observed when we considered the time as factor. Further studies are required to confirm these encouraging but preliminary findings, in order to consolidate rTMS as a valid tool to treat cocaine addiction.

Background: Cannabinoid consumption during pregnancy has been increasing on the wave of the broad-based legalisation of cannabis in Western countries, raising concern about the putative detrimental outcomes on foetal neurodevelopment. Indeed, since the endocannabinoid system regulates synaptic plasticity, emotional and cognitive processes from early stages of life interfering with it and other excitability endogenous modulators, such as neuropeptide Y (NPY), might contribute to the occurrence of a vulnerable phenotype later in life. Aims: This research investigated whether in utero exposure to Δ9-tetrahydrocannabinol (THC) may induce deficits in emotional/cognitive processes and alcohol vulnerability in adolescent offspring. NPY and excitatory postsynaptic density (PSD) machinery were measured as markers of neurobiological vulnerability. Methods: Following in utero THC exposure (2 mg/kg delivered subcutaneously), preadolescent male rat offspring were assessed for: behavioural reactivity in the open field test, neutral declarative memory and aversive limbic memory in the Novel Object and Emotional Object Recognition tests, immunofluorescence for NPY neurons and the PSD proteins Homer-1, 1b/c and 2 in the prefrontal cortex, amygdala and nucleus accumbens at adolescence (cohort 1); and instrumental learning, alcohol taking, relapse and conflict behaviour in the operant chamber throughout adolescence until early adulthood (cohort 2). Results: In utero THC-exposed adolescent rats showed: (a) increased locomotor activity; (b) no alteration in neutral declarative memory; (c) impaired aversive limbic memory; (d) decreased NPY-positive neurons in limbic regions; (e) region-specific variations in Homer-1, 1b/c and 2 immunoreactivity; (f) decreased instrumental learning and increased alcohol drinking, relapse and conflict behaviour in the operant chamber. Conclusion: Gestational THC impaired the formation of memory traces when integration between environmental encoding and emotional/motivational processing was required and promoted the development of alcohol-addictive behaviours. The abnormalities in NPY signalling and PSD make-up may represent the common neurobiological background, suggesting new targets for future research.

Conventional antidepressants are widely employed in several psychiatric and neurologic disorders, yet the mechanisms underlying their delayed and partial therapeutic effects are only gradually being understood. This narrative review provides an up-to-date overview of the interplay between antidepressant treatment and Brain-Derived Neurotrophic Factor (BDNF) signaling. In addition, the impact of nutritional, environmental and physiological factors on BDNF and the antidepressant response is outlined. This review underlines the necessity to include information on lifestyle choices in testing and developing antidepressant treatments in the future.