Identification of a Novel Population of Neuromedin S Expressing Neurons in the Ventral Tegmental Area That Promote Morphine-Elicited Behavior.

Abstract

Opioid use disorder constitutes a major health and economic burden, but our limited understanding of the underlying neurobiology impedes better interventions. Alteration in the activity and output of dopamine (DA) neurons in the ventral tegmental area (VTA) contributes to drug effects, but the mechanisms underlying these changes remain relatively unexplored. We used translating ribosome affinity purification (TRAP) and RNA sequencing to identify gene expression changes in mouse VTA DA neurons following chronic morphine exposure. We found that expression of the neuropeptide neuromedin S (NMS) is robustly increased in VTA DA neurons by morphine. Using an NMS-iCre driver line, we confirmed that a subset of VTA neurons express NMS and that chemogenetic modulation of VTA NMS neuron activity altered morphine responses in male and female mice. Specifically, VTA NMS neuronal activation promoted morphine locomotor activity while inhibition reduced morphine locomotor activity and conditioned place preference. Interestingly, these effects appear specific to morphine, as modulation of VTA NMS activity did not affect cocaine behaviors, consistent with our data that cocaine administration does not increase VTA Nms expression. Chemogenetic manipulation of VTA neurons that express glucagon-like peptide, a transcript also robustly increased in VTA DA neurons by morphine, does not alter morphine-elicited behavior, further highlighting the functional relevance of VTA NMS-expressing neurons. Together, our current data suggest that NMS-expressing neurons represent a novel subset of VTA neurons that may be functionally relevant for morphine responses and support the utility of cell-type-specific analyses like TRAP to identify neuronal adaptations underlying substance use disorder.