Dissecting ventral pallidal plasticity in punishment-resistant opioid self-administration

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PROJECT SUMMARY Opioid use disorder (OUD) is an escalating public health concern, and has resulted in over 550,000 overdose deaths between 1999 and 2020. Specifically, initial exposure to prescription opioids, such as oxycodone (OXY), has contributed to an average of 13,850 deaths annually since 2018 (Centers for Disease Control). While many individuals are able to use opioids as prescribed, a subset of individuals transition to compulsive drug use, which is defined as continued drug intake despite negative consequences, and is a hallmark feature of OUD. Similarly, most rodents will readily self-administer opioids, but will suppress their drug consumption when drug intake is paired with punishment such as foot shock (punishment-sensitive); while ~20-25% will persist in drug intake despite this punishment (punishment-resistant). Elucidating the neural mechanisms underlying individual differences in punishment-resistant drug seeking will be critical for understanding susceptibility to and treatment strategies for compulsive drug use. The ventral pallidum (VP) has emerged as a critical brain area for encoding the relative value and motivation for rewards and translating this motivation into reward seeking. The VP is a heterogeneous nucleus, with different populations playing opposing roles in appetitive behavior. Specifically, we and others have established that glutamatergic VP neurons (VPGlu) are crucial for constraining reward seeking in the face of aversive consequences, by modulating activity of downstream brain areas involved in punishment learning, including the lateral habenula (LHb) and rostromedial tegmental nucleus (RMTg). The objective of this proposal is to establish whether OXY- SA decreases the excitability, in vivo activity and synaptic output of VPGlu neurons, and determine if these adaptations are causally related to punishment-resistant OXY intake. Using complementary approaches of electrophysiology, calcium detection with fiber photometry and chemogenetic manipulations, we will establish whether OXY self-administration decreases excitability of VPGlu neurons, and whether this reduced activity is necessary and sufficient for the emergence of punishment-resistant OXY intake (Aim 1). We will next use electrophysiology and bidirectional optogenetic manipulations to determine whether reduced synaptic output from VPGlu neurons to the LHb or RMTg is causally related to punishment-resistant OXY intake (Aim 2). Finally, we will sequence actively translated mRNA from VPGlu neurons to determine gene networks that confer risk and protection against punishment-resistant OXY intake (Aim 3). This will also allow us to identify and validate potential pharmacological targets that could modulate VPGlu neuron activity in vivo as a therapeutic strategy. Our long-term goal is to elucidate the neural circuit basis of punishment-resistant opioid intake, and to leverage this understanding to develop neuromodulation therapies (such as deep brain stimulation with targeted pharmacology) to treat persistent drug intake despite negative consequences in patients with OUD.