Date of Award

Spring 1-1-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology & Neuroscience

First Advisor

Ryan K. Bachtell

Second Advisor

Steven F. Maier

Third Advisor

Robert L. Spencer

Fourth Advisor

Kent Hutchison

Fifth Advisor

Marissa A. Ehringer

Abstract

Drug-associated cues or pharmacological stimuli induce cocaine seeking by enhancing dopamine and glutamate neurotransmission in the nucleus accumbens (NAc). Adenosine is an inhibitory neuromodulator of dopamine and glutamate signaling and represents a viable target for decreasing relapse vulnerability. Postsynaptic adenosine A1 receptors and adenosine A2A receptors co-localize with dopamine receptors on distinct populations of medium spiny neurons in the NAc. The co-localization of dopamine and adenosine receptors is meaningful in that adenosine receptor stimulation antagonizes dopamine receptor signaling and alters the activity of NAc output pathways. Presynaptic adenosine receptors are expressed on glutamate terminals in the NAc where A1 receptors inhibit and A2A receptors enhance glutamate release in the NAc. The overarching goal of these studies was to determine the how distinct populations of adenosine receptors modulate striatal signaling to influence cocaine seeking. Our results indicate that adenosine receptors oppositely modulate cocaine seeking depending on the receptor subtype and their synaptic locale. Postsynaptic adenosine A2A receptor stimulation in the NAc decreases cocaine seeking by disrupting dopamine D2 receptor signaling in the NAc. Postsynaptic blockade of adenosine A2A receptors enhances cocaine seeking by facilitating dopamine D2 receptor signaling. Blockade of presynaptic adenosine A2A receptors, on the other hand, reduces cocaine seeking, potentially by tempering augmented glutamate release that drives reinstatement. Lastly, adenosine A1 receptor stimulation or presynaptic adenosine A2A receptor blockade during extinction produces long-term changes in relapse susceptibility. The findings suggest that modulating specific populations of NAc adenosine receptors are influential in cocaine seeking and may represent viable pharmacotherapeutic strategies.

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