Date of Award

2022

Embargo Period

6-12-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Thomas C. Jhou

Second Advisor

Lawrence J. Chandler

Third Advisor

Lisa M. McTeague

Fourth Advisor

Carmela M. Reichel

Fifth Advisor

Bryan K. Tolliver

Abstract

Although cocaine and other psychostimulants are highly rewarding, they also produce aversive effects that influence drug-seeking, and that are stronger in some individuals than others for poorly understood reasons. We now find in rats that cocaine depolarizes neurons of the rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons, and a driver of punishment learning. This activation is mediated by post-synaptic serotonin 2C receptors, and is particularly strong in subsets of animals having heightened aversive responses to cocaine, among whom it slows the initial acquisition of cocaine self-administration and reduced cue-induced relapse for cocaine after extinction. These resilience phenotypes are lost upon delivery into RMTg, but not adjacent sites, of 5-HT2CR antagonist or shRNA-mediated knockdown of this receptor. Hence, 5-HT2CRs in RMTg may contribute to innate, and individually variable, protection against cocaine-seeking.

Rights

All rights reserved. Copyright is held by the author.

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