Mu opioid receptor expression by nucleus accumbens inhibitory interneurons promotes affiliative social behavior

Mu opioid receptors in the nucleus accumbens regulate motivated behavior, including pursuit of natural rewards like social interaction as well as sensitivity to exogenous opioids. However, the specific circuit elements where mu opioid receptor expression promotes these motivated behaviors remain unclear. In mice of both sexes, we used a suite of genetic and viral strategies to conditionally delete mu opioid receptor expression from major neuron types in the nucleus accumbens, as well as monosynaptic inputs to this brain region. We pinpointed local inhibitory interneurons as an essential site of mu opioid receptor expression for typical social behavior. Mu opioid receptor deletion from inhibitory interneurons decreased both social interaction and preference, while shifting the ratio between synaptic excitation and inhibition onto medium spiny projection neurons, but did not alter exogenous opioid sensitivity. Conversely, mu opioid receptor deletion from medium spiny neurons altered exogenous opioid sensitivity but not social interaction, revealing a double-dissociation in the behavioral functions of mu opioid receptors expressed by nucleus accumbens projection neurons versus interneurons. Chemogenetic activation of inhibitory interneurons in the nucleus accumbens also decreased social interaction, mimicking the effect of mu opioid receptor deletion from these cells. Our findings suggest that circuit-specific engagement of mu opioid receptors could circumvent the risk of misuse associated with conventional exogenous opioids, with important implications for the pathophysiology and treatment of neuropsychiatric conditions involving social differences.