Social reward outcompetes drug seeking dopaminergic ensembles to prevent relapse

Abstract

Abstract Drugs of abuse promote substance use disorder (SUD) by hijacking mesolimbic circuits that normally process natural rewards. Among these, social rewards exhibit therapeutic potential, but the underlying neural substrates remain unclear. Using a multimodal approach integrating in vivo single-neuron calcium imaging, optogenetic manipulation, and electrophysiology in male rats, we identified two distinct dopaminergic ensembles in the ventral tegmental area (VTA) that respectively encode social reward and drug seeking. Notably, these antagonistic ensembles exert reciprocal influence through competitive interactions that shape behavioral outcomes. Furthermore, circuit mapping revealed divergent connectivity patterns, with social reward-responsive dopaminergic ensembles receiving preferential input from the dorsal raphe nucleus (DRN). Activation of the DRN-VTA pathway recapitulates the protective effects of social reward against drug seeking. In this study, we uncovered a dynamic competition between functionally specialized dopaminergic ensembles through which social reward attenuates drug seeking, offering insights that may inform development of novel strategies for SUD treatment.