Date of Award

Spring 1-1-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Ryan K. Bachtell

Second Advisor

Robert L. Spencer

Third Advisor

Michael Saddoris

Fourth Advisor

McKell Carter

Fifth Advisor

Jerry A. Stitzel

Abstract

Drug addiction is a chronic relapsing disorder affecting millions of people. No effective treatment exists for psychostimulant use disorder, stressing the importance to investigate underlying mechanisms mediating this disorder. Psychostimulants like cocaine and methamphetamine (MA) impact behavior by modulating neurotransmitter signaling systems in the nucleus accumbens (NAc). In this region, converging dopamine and glutamate signals interact with receptors to influence cellular functioning. The neuromodulator, adenosine, has received attention regarding its ability to affect both dopamine and glutamate signaling through converging intracellular signaling associated with metabotropic receptor proteins. Adenosine A2A receptors (A2ARs) and dopamine D4 receptors (D4s) are two receptors expressed in the striatal and cortical areas, respectively, that are hypothesized to influence psychostimulant-induced behavior.

A series of experiments were designed to investigate how D4s and subpopulations of A2ARs influenced psychostimulant-induced behavior. The results show that specific activation or blockade of D4s decrease locomotor activity but that this reduction disappears when D4s are activated or antagonized prior to psychostimulant treatments. Unlike D4s that have a complicated role in psychostimulant-induced behaviors, A2AR activity in the NAc has been directly implicated in affecting these behaviors. We show that pretreatments with two A2AR antagonists previously shown to block pre- and postsynaptic A2ARs resulted in distinct drug-induced locomotor activity. These behaviors differed between cocaine and MA such that the presynaptic A2AR antagonist, SCH 442416, blunted the expression of cocaine sensitization, while pretreatments of the postsynaptic A2AR antagonist, KW 6002, augmented locomotor activity only prior to acute cocaine or MA. The mechanisms underlying these observed behaviors were also investigated and suggest that these effects were mediated in a NAc-independent manner. These experiments suggest that presynaptic A2ARs may be a viable pharmacotherapeutic target for treating cocaine addiction.

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