Date of Award

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Gary Aston-Jones

Second Advisor

Ronald E. See

Third Advisor

Carmela M. Reichel

Fourth Advisor

L. Judson Chandler

Fifth Advisor

Patrick J. Mulholland

Sixth Advisor

Stan B. Floresco

Abstract

Human and animal studies suggest that females differ in their motivation to use methamphetamine (meth), and have increased propensity to relapse. However, addiction pharmacotherapies have primarily only been tested in males, which may not accurately predict treatment outcomes in females. Evidence suggests that oxytocin, an endogenous peptide well known for its role in social behaviors and childbirth, is a promising addiction pharmacotherapy. This dissertation first examines sex differences in the effect of oxytocin to decrease meth and sucrose seeking. Our data indicate that systemic oxytocin decreased responding for meth differentially in males and females on a progressive ratio schedule of reinforcement (a measure of motivation) in females but not males, although it reduced reinstatement of meth seeking similarly in both sexes. To further examine these sex differences, we next employed a translational within-session behavioral-economic (BE) model designed specifically for meth self administration. The BE paradigm allows for measurement of drug demand at high effort (motivation; α), normalized based on intake at low effort (baseline consumption; Q0) within the same session. This approach also allowed us to assess individual variability in meth demand in relation to relapse behaviors, and in response to oxytocin administration. Our rodent BE paradigm was modeled after BE procedures commonly used to assess motivation for reward in humans and non-human primates. Importantly, the same BE variables (α, Q0) are assessed across species, and these variables have been shown to predict later relapse behavior. Therefore, the translational potential of preclinical BE studies is particularly strong. We showed that this BE model can predict relapse-like behaviors, and that systemic oxytocin acts similarly in both males and females to decrease demand (i.e., motivation) for meth and attenuated reinstatement to meth seeking. We also demonstrated that oxytocin is most effective at decreasing meth seeking in rats with the strongest addiction phenotype. Finally, we showed that systemic oxytocin acts via a central mechanism, and more specifically through actions in the NAc core. Together these results demonstrate that oxytocin modifies multiple meth-seeking behaviors, show the efficacy of oxytocin as a pharmacotherapy for addiction in both sexes, and characterize the effects of oxytocin on mesolimbic brain circuitry implicated in addiction. Overall, these data indicate that oxytocin-based therapies would be a promising treatment approach for meth addiction in humans.

Rights

All rights reserved. Copyright is held by the author.

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