Alcohol dependence is a major public health concern. Despite the FDA’s approval of multiple anti-relapse drugs, relapse rates remain unacceptably high. Furthermore, cognitive deficits among chronic drinkers are evident and are suggested to contribute to relapse risk. Current evidence suggests that several critical features of alcoholism and alcohol-associated neurodegeneration are mechanistically linked to glutamatergic actions; specifically, they appear positively affected by glutamatergic inhibition, particularly inhibition via polyamine modulation of a subpopulation of n-methyl-d-aspartate receptors. The current project was designed to evaluate the performance of two putative polyamine modulators (JR-220 and CP-101,606) in a variety of screens designed to identify the potential to reduce withdrawal severity, neurotoxicity and relapse risk. Screens included a complex organotypic screen designed to assess neuroprotective potential (Experiment 1), a simple behavioral screen designed to assess withdrawal severity (Experiment 2) as well as several more complex behavioral screens designed to examine cue-conditioning during withdrawal (Experiment 3), relapse behavior (Experiment 4), stress-associated consumption (Experiment 5) and binge-like consumption (Experiment 6). An additional open field experiment (Experiment 7) was conducted in order to address interpretational issues concerning activity in Experiments 2-6. Finally, as a first step in moving beyond simple screening, we expanded our binge screen to adhere more closely to an established, validated model of binge consumption (Experiment 8). While some interpretational issues were noted, taken together, the results from these experiments provide strong evidence for both drugs as potential pharmacotherapies for alcoholism and further implicate polyamines and NR2B subunits as critical mechanisms in ETOH consumption and withdrawal.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:gradschool_diss-1854 |
| Date | 01 January 2011 |
| Creators | Lewis, J. Ben |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | University of Kentucky Doctoral Dissertations |
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