Conditioned social preference and reward value of activating oxytocin-receptor-expressing ventral tegmental area neurons following repeated daily binge ethanol intake.

BACKGROUND: Individuals with alcohol use disorder (AUD) exhibit a disruption of social behavior and dysregulation of oxytocin signaling in the brain, possibly reflecting decreased activation of oxytocin receptors (OxTRs) in reward pathways in response to social stimuli. We hypothesize that daily binge ethanol intake causes a deficit in social reward and oxytocin signaling in the ventral tegmental area (VTA). METHODS: After 9 weeks of daily binge ethanol intake (blood ethanol concentration >80 mg%), OxTR-cre mice underwent conditioned place preference for social reward. Separate groups of mice were tested for the effects of binge ethanol on voluntary social interactions, food reward, locomotion, and anxiety-like behaviors. A subset of mice underwent transfection of OxTR-expressing VTA neurons (VTAOxtr ) with a light-sensitive opsin, followed by operant training to respond to light delivered to VTA. RESULTS: Ethanol-naïve male mice increased the time spent on the side previously paired with novel mice while ethanol-treated mice did not. Binge ethanol did not affect conditioned place preference for food reward in males, but this response was weakened in ethanol-treated females. Ethanol treatment also caused a sex-specific impairment of voluntary social interactions with novel mice. There were minimal differences between groups in measures of anxiety and locomotion. Ethanol-naïve mice had significantly greater operant responding for activation of VTAOxtr than sham-transfected mice but ethanol-treated mice did not. There was no difference in the number of VTAOxtr after binge ethanol. CONCLUSIONS: Daily binge ethanol causes social reward deficits that cannot be explained by nonspecific effects on other behaviors, at least in males. Only ethanol-naïve mice exhibited positive reinforcement caused by activation of VTAOxtr while daily binge ethanol did not alter the number of VTAOxtr in either males or females. Thus, subtle dysregulation of VTAOxtr function may be related to the social reward deficits caused by daily binge ethanol.

Chronic Voluntary Binge Ethanol Consumption Causes Sex-Specific Differences in Microglial Signaling Pathways and Withdrawal-associated Behaviors in Mice.

BACKGROUND: Microglia are the resident immune cells in the brain where they play essential roles in the development and maintenance of physiological functions of this organ. Aberrant activation of microglia is speculated to be involved in the pathogenesis of a variety of neurological disorders, including alcohol use disorders. Repeated binge ethanol (EtOH) consumption can have a profound impact on the function and integrity of the brain resulting in changes in behaviors such as withdrawal and reward. However, the microglial molecular and cellular pathways associated with EtOH binge consumption remain poorly understood. METHOD: In this study, adult C57BL/6J male and female mice were subjected daily to a gelatin-based drinking-in-the-dark voluntary EtOH consumption paradigm (3 h/d for 4 months) to characterize EtOH consumption and withdrawal-associated and anxiety-like behaviors. Brain microglia were isolated at the end and analyzed for protein expression profile changes using unbiased mass spectrometry-based proteomic analysis. RESULTS: Both male and female mice consistently consumed binge quantities of EtOH daily, resulting in blood EtOH levels > 80 mg/dl measured at the end of the 3-hour daily consumption period. Although female mice consumed a significantly greater amount of EtOH than male mice, EtOH withdrawal-associated anxiety-like behaviors measured by marble-burying, light-dark box, and elevated plus maze tests were predominantly observed in male mice. Proteomic analysis of microglia isolated from the brains of animals at the end of the 4-month binge EtOH consumption identified 117 and 37 proteins that were significantly up- or downregulated in EtOH-exposed male and female mice, respectively, compared to their pair-fed controls. Protein expression profile-based pathway analysis identified several cellular pathways that may underlie the sex-specific and EtOH withdrawal-associated behavioral abnormalities. CONCLUSION: Taken together, our findings revealed sex-specific changes in EtOH withdrawal-associated behaviors and signaling pathways in the mouse brain microglia and may help advance our understanding of the molecular, cellular, and behavioral changes related to human binge EtOH consumption.