Abstract

Opioid use disorder is an urgent public health crisis in the United States. Over 800,000 Americans have died from opioid-related overdoses since 2000. Nearly 30% of people who misuse opioids begin with prescription oral opioids, such as oxycodone, and continue misusing to avoid the immediate aversive state of withdrawal and the persistent dysphoria associated with protracted abstinence from opioids. The persistency of these dysphoric symptoms increases the risk of relapse even after long periods of abstinence. Treatment for opioid use disorder currently consists of pharmacological opioid treatment to reduce withdrawal symptoms and behavioral counseling. However, these strategies have significant real-world limitations such as social stigma, cost, and lack of availability and infrastructure. To develop treatments and preventative strategies for opioid use disorder, a better understanding of the neural mechanisms that are affected by long-term opioid use and abstinence is needed. The ventral pallidum (VP) contributes to relapse behavior after withdrawal, as it is required for motivated drug seeking and is associated with anhedonia, a symptom of withdrawal. Recent studies have shown that distinct populations of VP neurons have opposing roles in reward processing; positively-valenced stimuli is primarily encoded by inhibitory VP neurons, while the recently defined glutamatergic subpopulation (VPGlu) constrains reward seeking and has a critical role in negative stimuli integration and decision making. VPGlu neurons also express opioid receptors and project to the lateral habenula (LHb), a nucleus that indirectly inhibits dopamine release from the ventral tegmental area and exhibits hyperexcitability in drug withdrawal. Thus, VPGlu neurons are uniquely situated to contribute to the processing of aversion and reward seeking in the context of opioid use disorder. Using an oxycodone self-administration protocol, we investigated the effect of opioid consumption and abstinence on VPGlu neurons using ex vivo electrophysiology and in vivo Ca2+ activity recording. We hypothesized that the continual inhibition of VPGlu neurons by opioid self-administration would lead to compensatory actions to maintain baseline levels of activity and neurotransmitter release in these neurons. This would lead VPGlu neurons to be more excitable, active, and release more glutamate onto LHb neurons following self-administration of opioids. In this dissertation, we show how oxycodone self-administration changes the electrophysiological intrinsic excitability and opioid sensitivity of VPGlu neurons and the VPGlu:LHb synapse. This work defines VPGlu neurons before and after oxycodone self-administration to render a comprehensive view of these neurons over an opioid use time course. Based on the results herein, this dissertation furthers the understanding of how opioids affect the aversion-promoting component of the mesolimbic reward system and provides an avenue for future interventional studies.

Committee Chair

Meaghan Creed

Committee Members

Federica Lucantonio; Jasper Heinsbroek; Martha Bagnall; Ream Al-Hasani

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-8-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-8579-8028

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Available for download on Wednesday, May 06, 2026

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Biology Commons

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