Date of Award

2024

Embargo Period

3-12-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Medicine

Additional College

College of Graduate Studies

First Advisor

Carmela M. Reichel

Second Advisor

Christopher W. Cowan

Third Advisor

Michael D. Scofield

Fourth Advisor

Jennifer A. Rinker

Fifth Advisor

Aimee L. McRae-Clark

Sixth Advisor

Ronald E. See

Abstract

We are in the midst of an opioid use disorder (OUD) epidemic. While several treatments mitigate a range of factors contributing to return to use, or relapse, the power of drug-conditioned environmental cues to precipitate relapse have not been adequately addressed. One treatment modality targeting cue reactivity, cue exposure therapy (CET), exacerbated relapse in individuals with OUD, perhaps due to a deficit in extinction memory recall (EMR). Here, EMR is the ability to override the drug-cue association and prevent relapse. Interest remains in combatting cue-induced relapse, potentially by introducing a pharmacologic adjunct with CET to enhance EMR. In the following chapters, this dissertation will test the prospect for estrogen signaling to enhance heroin-cue EMR in a preclinical model of OUD.

After an introduction to OUD and estrogen signaling (Chapter 1), Chapter 2 tests the effects of sex and gonadal hormones on several aspects of heroin self-administration. This revealed that females took more heroin and responded more for heroin cues than males. Based on prior literature indicating that estrogen receptor β (ERβ) may impact fear EMR, Chapters 3 and 4 tested the effects of systemic ERβ agonism on heroin- and sucrose-cue EMR after varying periods of abstinence. Notably, ERβ agonism reliably enhanced heroin-cue EMR in both sexes without affecting sucrose-cue EMR.

To uncover the neurobiological underpinnings of ERβ’s effect, the remaining experiments examined how estrogen signaling in the basolateral amygdala (BLA) impacts heroin-cue EMR. Chapter 5 introduces the amygdala and evaluates literature implicating the BLA in mediating ERβ’s effects on heroin-cue EMR. This is tested in Chapter 6, wherein ERβ agonism in the BLA enhanced heroin-cue EMR in females only. Reinforcingly, ERβ antagonism in the BLA impaired EMR in females while, unexpectedly, ERα antagonism disrupted EMR in males. In fact, inhibition of estrogen synthesis in the BLA had similar disrupting effects on heroin-cue EMR (Chapter 8). This sex-specific contribution of ERβ in the BLA may be driven by differences in ERβ expression in a subregion of the BLA (Chapter 9). Collectively, these results indicate that ERβ agonists can enhance heroin-cue EMR and are, therefore, potential adjuncts to CET to treat OUD.

Rights

Copyright is held by the author. All rights reserved.

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