Dissecting the neurobiological basis of social control over alcohol self-administration - SUMMARY Alcohol Use Disorder (AUD) is a global public health issue for which more effective treatments are urgently needed. While it is widely appreciated that social context is a powerful modulator of human alcohol self- administration. this factor has been largely ignored in preclinical AUD research. The development of an alcohol self-administration model which allows experimental control over social context and tight control over alcohol self-administration stands to reveal new information about the neurobiological bases of AUD. Specifically, the present proposal seeks to experimentally determine the nature of the interaction between social interaction and self-administered alcohol (i.e., complimentary vs. substitute goods) using a simple-to-implement preclinical AUD model that allows the study of social-context as a factor regulating alcohol drinking behavior. Further, we seek to determine how this interaction is changed by the development of alcohol dependence, during which we hypothesize alcohol reinforcement transitions from being a mainly-positive reinforcer to a mainly- negative reinforcer. Additionally, we will determine how male and female rats differ in terms of social context control over alcohol self-administration behavior. We also propose to study the inverse relationship of this interaction; how alcohol self-administration, alcohol dependence, and biological sex shape the nature and quality of social interaction. To begin to dissect the neurobiological basis of the interaction between social context and alcohol self-administration behavior, we propose to combine several neurohistochemical techniques to determine the brain regions which contain neurons strongly activated during alcohol-seeking behavior in social vs. non-social contexts (i.e., express the immediate early gene cFos). Further, we seek to determine how this brain-wide activity maps onto the neurocircuitry of the prototypical social neuropeptide, oxytocin (i.e., to co-detect neurons which synthesize the oxytocin peptide and/or which express the oxytocin receptor). Finally, we propose to leverage a combination of novel AAV technologies, optogenetics, and pharmacology, to test the functional relevance of neurons of the brain oxytocin neurocircuitry to control alcohol self-administration behavior in social vs. non-social contexts. This highly innovative research proposal is also highly feasible given the expertise and technologies offered by this unique team of researchers. Successful completion of this research project is expected to have a high impact and a sustained impact on preclinical AUD research in broad terms, by 1. providing a means to systematically examine the neurobiology of AUD from the largely ignored perspective of social context, 2. Identifying the neurobiological basis for the control of social context over alcohol consumption, and 3. Determine a causal role for neurons of the brain oxytocin system in the modulation of alcohol consumption across social vs. non-social contexts. Ultimately, by providing new information about the neurobiology of AUD, this project stands to move the field toward the generation of novel candidate treatments for AUD which have the best chance to successfully make the leap across the pre-clinical to clinical translational divide.
