Date Available

11-2-2013

Year of Publication

2013

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Arts and Sciences

Department/School/Program

Psychology

First Advisor

Dr. Mark Prendergast

Abstract

Alcohol abuse disorders (AUD) represent a serious worldwide health problem with far reaching social, financial, and interpersonal implications. One of the most devastating facets of these disorders is the propensity to relapse following periods of abstinence. Ethanol withdrawal (EWD) is believed to promote relapse by increasing anxiety and craving, and may contribute to the development of cognitive decline associated with long-term dependence. Clinical data suggest that stress also plays a main role in both the development of AUD as well as relapse to drinking. As a physiological stressor, EtOH elevates levels of stress hormones (cortisol in humans, corticosterone (CORT) in the rat). Both CORT and EtOH have been shown to alter the composition, function, and activity of the N-methyl-D-aspartate (NMDA) receptor, and in particular, the NR2B subunit of this receptor. These alterations have been suggested to mediate EWD, which may negatively impact abstinence rates. This synergistic interaction between EtOH and CORT may present a therapeutic target for the treatment of EWD. In fact, data suggest that blocking the glucocorticoid receptor, which is a main target for CORT, with RU-486 could promote abstinence, as treatment with the drug has been shown to reduce consumption and the development dependence, as well as the severity of EWD and the cognitive deficits following EWD. However, these latter effects have not been validated in models of voluntary EtOH consumption. As there is considerable evidence that active versus passive intake can significantly impact neuroadaptations to ethanol this is an important consideration. These studies sought to characterize consumption and evaluate the development of dependence in a chronic voluntary model of intermittent access (IA) to EtOH. CORT plasma levels and protein expression of the glucocorticoid and NR2B receptors were measured during and/or following exposure. Finally, to assess the role of CORT in EtOH consumption and the development of dependence, the glucocorticoid receptor antagonist ORG-34517 was administered during access to EtOH. IA access to 20% EtOH produced varying levels of consumption (2.0-6.7g/kg/24hr exposure) and blood EtOH levels (6.3-116.9 mg/dl), but did not significantly affect food consumption or weight gain. Baseline CORT levels were found to be predictive of subsequent EtOH consumption and levels of consumption were sufficient to elevate CORT levels following one hour of EtOH exposure. Further, IA to EtOH was sufficient to produce dependence, as measured by elevations in the acoustic startle reflex following 26 hours and five days of withdrawal. No alteration in protein expression was observed regarding either the NR2B or glucocorticoid receptors and exposure to ORG-34517 had no effect on consumption or withdrawal.

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