Modulation of 5-HT release by dynorphin mediates social deficits during opioid withdrawal

Social isolation during opioid withdrawal is a major contributor to the current opioid addiction crisis. We find that sociability deficits during protracted opioid withdrawal in mice require activation of kappa opioid recep-tors (KORs) in the nucleus accumbens (NAc) medial shell. Blockade of release from dynorphin (Pdyn)-ex-pressing dorsal raphe neurons (DRPdyn), but not from NAcPdyn neurons, prevents these deficits in prosocial behaviors. Conversely, optogenetic activation of DRPdyn neurons reproduced NAc KOR-dependent de-creases in sociability. Deletion of KORs from serotonin (5-HT) neurons, but not from NAc neurons or dopa-mine (DA) neurons, prevented sociability deficits during withdrawal. Finally, measurements with the geneti-cally encoded GRAB5-HT sensor revealed that during withdrawal KORs block the NAc 5-HT release that normally occurs during social interactions. These results define a neuromodulatory mechanism that is engaged during protracted opioid withdrawal to induce maladaptive deficits in prosocial behaviors, which in humans contribute to relapse.