SOCIAL INTERACTION SUPPRESSES COCAINE RELAPSE BY REGULATING DAERGIC ENGRAM INPUT OF VENTRAL TEGMENTAL AREA

Abstract Purpose Addiction is a chronic relapsing brain disease, characterized by a high susceptibility to relapse once returns to the original living environment even after an extended period of abstinence. Positive social interactions are believed to have therapeutic potential in managing drug addiction by shifting the drug reward back onto social reward. However, the neural mechanisms underlying social interaction’ s therapeutic effects against relapse are poorly understood. The dopamine (DA) activity of Ventral tegmental area (VTA) mediates both the reinforcing properties of social reward and drugs of abuse. Therefore, we hypothesized that distinct subpopulations of DAergic neurons in the VTA may play different roles in the process of social anti-relapse. Methods We employed the cocaine self- administration as a relapse model in rats, and combined Targeted Recombination in Active Populations (TRAP), immunofluorescence, fiber photometry recording, and chemical genetics to explore the involvement of subpopulations of DAergic neurons during social interaction-mediated relapse prevention. Results We found that social interaction significantly inhibited the spontaneous recovery of cocaine seeking after cocaine self-administration extinction training in rats. While both social interaction and relapse of cocaine seeking reliably elicited obvious Ca2+ level increase in the TH neurons of VTA and induced DA relapse in nucleus accumbens (NAc), both the increase of Ca2+ level in the TH neurons of VTA and DA release in NAc induced by active cocaine relapse were significantly reduced after social interaction. Furthermore, the subpopulations of DAergic neurons in the VTA which encoded social interaction and relapse were distinct and anatomically segregated. Lastly, capturing and reactivating the specific subpopulation of DAergic neurons in the VTA encoding social interaction significantly inhibited cocaine relapse. Conclusion This study provided the evidence that distinct subpopulations of DAergic neurons in the VTA are involved in social interaction and relapse, and selective activation of the memory engram of social interaction in the VTA effectively inhibited drug relapse. Future studies will explore the input of DAergic neurons engram in the process of social interaction’ s therapeutic effects against cocaine relapse by combining mini scope, cross-synaptic engram tracer, brain patch clamp, and optogenetic, and reveal the circuitry mechanism of natural reward and drug reward interaction.