Date of Award

Fall 2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Mantsch, John R.

Second Advisor

Baker, David A.

Third Advisor

Gasser, Paul J.

Abstract

Cocaine addiction represents a tremendous health and financial burden on our society and the high rate of relapse to cocaine use in abstinent addicts represents a major barrier to effective therapy. Thus, understanding the factors that contribute to relapse and the underlying neurobiological processes is important for guiding the development of treatment for addiction. Stressful life events often trigger drug use in recovering addicts. The contribution of stress to drug use is problematic due to the unpredictable and often uncontrollable nature of stress. A growing literature indicates that norepinephrine and corticotropin releasing factor (CRF) in the brain play key roles in stress interactions with motivational neurocircuitry that mediate stress-induced drug seeking. Previous work from our lab has demonstrated that activation of the CRFR1 receptor within the ventral tegmental area (VTA) is both necessary and sufficient for drug-seeking behavior during periods of stress. However, the afferent CRF projection into the VTA, and how CRF affects the neurocircuitry of VTA to evoke stress-induced relapse are poorly understood. We report that stress-induced cocaine use involves a beta-2 adrenergic receptor-regulated CRF pathway from the ventral bed nucleus of the stria terminalis to the VTA and a CRFR1 receptor-regulated dopaminergic pathway to the prelimbic cortex. It is hypothesized that dopamine released into the prelimbic cortex activates dopamine D1 receptors on pyramidal neurons that comprise a glutamatergic projection to the nucleus accumbens core that is critical for relapse to drug use in abstinent cocaine addicts. It is also reported that the ability of stressors to trigger drug use is determined by the amount and pattern of prior drug use. Findings suggesting that excessive cocaine use establishes susceptibility to stress-induced relapse by recruiting CRF regulation of this key stressor-responsive mesocortical dopaminergic pathway through increased CRFR1 expression are described. This dissertation defines a key pathway through which stress can promotes relapse and describes its recruitment as result of repeated excessive drug use. Understanding the processes through which stress contributes to cocaine seeking in these rodent models should facilitate translational work aimed targeting these mechanisms clinically and therefore the development of new medications or approaches managing for addiction.

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