Behavioral and neurobiological mechanisms of reciprocal social interactions in Substance Use Disorders - Project Summary Social interactions are fundamental to our daily lives, shaping our identities, relationships, and societies. These interactions are complex, involving verbal and nonverbal cues, cultural norms, and individual differences, typically following a give-and-take dynamic with expectations of reciprocation. However, these dynamics are disrupted in substance use disorders (SUDs), where higher social integration is linked to lower drug abuse and relapse risk. As drug use escalates from recreational to compulsive, individuals often experience social impairment, marginalization, stigmatization, and isolation, which can further promote drug use. Despite the recognized importance of social factors in SUDs, integrating complex social interactions into neuroscientific research remains challenging, potentially widening the gap between preclinical research and clinical applications. To address this, we developed a behavioral model where a resident rat initiates interaction by pressing a lever to activate cues for the partner, who then reciprocates by pressing another lever, leading to social interaction. This model aims to mimic human conditions more closely by studying how drug use leads to progressive social isolation when partners do not reciprocate social interactions, while the drug use itself becomes increasingly compulsive for the residents. In Aim 1, we will identify heroin-vulnerable rats and observe their social interactions versus heroin choice as their drug use escalates, predicting that partner- induced social isolation will increase in compulsive rats, further promoting heroin choice. Advanced machine learning methods will be used to capture complex social behaviors, with the hypothesis that compulsive rats will exhibit more 'frustration' behaviors (e.g., self-grooming, time spent by the closed door) compared to low- compulsive rats that can engage in reciprocal social interactions. Based on preliminary data showing the involvement of the norepinephrine system in reciprocal social interactions, Aim 2 will use a combination of TH- cre rats and chemogenetic approaches to manipulate norepinephrine in the locus coeruleus of partner rats. This manipulation is expected to promote reciprocal social interaction and reduce heroin choice in resident rats, highlighting the importance of social interactions in SUDs. Unlike traditional studies focusing on drug- administering rats, this approach demonstrates the critical role of social interaction by performing neurobiological manipulations on partner rats, ultimately influencing the behavior of the drug-using rats.
