600. TARGETING THE VENTRAL PALLIDUM TO TREAT OPIOID USE DISORDER

Abstract Background Withdrawal from opioids is associated with a highly aversive affective state, and avoidance of this state is a main reason people with opioid use disorder continue to use or relapse to opioids. Activity in the ventral pallidum (VP) is necessary for opioid relapse after withdrawal. Recent studies from our group and others have shown that glutamatergic VP neurons (VPGlu) constitute a unique subpopulation of VP neurons, and that VPGlu activity constrains reward seeking, particularly in decision-making tasks where negative consequences are associated with choosing a reward. However, how self-administration and withdrawal from prescription opioids alters the function of VPGlu neurons and their activity in conflicted decision-making tasks is completely unknown. Aims & Objectives To determine how self-administraiton of opioids alters function of ventral pallidal circuits, specifically the glutamatergic ventral pallidal neurons. As a corollary, how do changes in these circuits drive changes in decision making in the context of opioid use disorder. Method With fluorescent in situ hybridization, we discovered that VPGlu neurons are enriched in mu opioid receptors. Patch-clamp electrophysiology experiments revealed that application of mu opioid agonists decreased excitability of VPGlu neurons. Results Opioid self-administration and protracted abstinence from oxycodone increased the intrinsic excitability of VPGlu neurons, and potentiated their synaptic output to the lateral habenula. Using in vivo calcium imaging we investigated the basal activity of VPGlu neurons throughout oxycodone self-administration, we determined that spontaneous in vivo activity of these neurons is elevated following opioid exposure. Discussion & Conclusions Our results establish that oxycodone self administration increases the excitatory synaptic drive onto glutamatergic VP neurons, increases their excitability and potentiates their synaptic output to the VP. Given our previous work showing that activation of VPGlu neurons is highly aversive, we hypothesize that these opioid-induced adaptations contribute to the aversive state of drug withdrawal that drives opioid relapse through negative reinforcement. Our results also suggest that the excitability and synaptic output of these cells is reduced by mu-opioid receptor stimulation, proposing a potential mechanism by which opioids alter decision making under conditions of conflict.