Dissecting the contribution of glutamatergic ventral pallidal neurons to the aversive state of opioid withdrawal

项目总结

PROJECT SUMMARY Opioid use disorder is an urgent public health crisis in the U.S. and roughly 30% of Americans prescribed opioids misuse their medications. The overwhelming reason people with opioid use disorder continue taking opioids is to avoid withdrawal. Opioid withdrawal is physically painful and emotionally exhausting. Despite the inherently chronic relapsing nature of drug abuse and withdrawal, studies of how long-term opioid use alters the aversion circuits of the brain are surprisingly limited compared to those studying the reward circuits. Dysfunction of mesolimbic circuits, which includes the ventral pallidum (VP) and its downstream targets, has been implicated in a wide range of substance abuse disorders, including opioid use disorder, but it is not known how opioid use- induced adaptations arise in these brain areas. One hypothesis is that withdrawal from chronic use of opioids may prompt adaptations in aversion-processing circuits that generate a higher sensitivity to aversive stimuli and mediate the general negative affective state associated with withdrawal; thus leading to increased stress and subsequent relapse. The VP is especially well-positioned to mediate adaptations of aversion circuits in opioid use disorder. VP neurons receive input from reward and aversion encoding structures and modulate aversion centers of the brain, a primary output being the lateral habenula (LHb). Furthermore, a recently discovered subset of VP neurons (VPGlu) has been shown to encode aversion in reward-related contexts. In this proposal, I plan to use a multi-faceted approach to investigate opioid use-induced adaptations of LHb-projecting VP (VPGluLHb) neurons in mice. I hypothesize that VPGlu neurons are hyperactive and more responsive to noxious stimuli in protracted opioid withdrawal, and that opioid withdrawal potentiates transmission at VPGluLHb synapses. Lastly, I expect that VPGlu neuronal activity confers sensitivity to negative outcomes and that this response is heighted following opioid withdrawal. I propose to test each of these hypotheses in specific aims using in vivo and ex vivo electrophysiology, optogenetics, and behavioral techniques to evaluate VPGluLHb activity and plasticity as potential mechanisms underlying enhanced sensitivity to aversive outcomes and events. Successful completion of these aims will inform future therapeutic interventions to treat the negative affective state of opioid withdrawal to allow for successful treatment of opioid use disorder.