The present exploratory R21 grant proposal builds on our NIAAA funded research showing that increased atmospheric pressure is a direct, mechanistic antagonist for ethanol that blocks and reverses a broad spectrum of ethanol's behavioral effects, and ethanol's action on neurotransmitter-gated receptors, without causing changes in behavior or baseline receptor function. These qualities of pressure antagonism of ethanol hold out the possibility of developing therapeutic agents that antagonize ethanol without causing adverse effects. However, we do not feel that pressure per se represents a viable therapeutic tool for treating alcoholism. Therefore, the present proposal represents the first step in a strategy for translating current knowledge regarding pressure antagonism of ethanol to the development of novel pharmacotherapeutic agents for treating alcoholism. The long-term goal of the proposed work is to develop pharmacological agents that mimic pressure and antagonize ethanol's action on molecular targets within receptors without causing changes in normal function of the receptors or behavior. The primary goal of this proposal is to begin to determine the molecular mechanism of pressure antagonism of ethanol and potential targets for pharmacological agents.
Specific Aim 1. Identify the molecular sites of action of pressure antagonism of ethanol in glycine, GABAA and GABAP receptors.
Aim I will be accomplished by combining molecular approaches with hyperbaric two-electrode voltage clamp techniques in Xenopus oocytes recently developed by our laboratory. Phase I will test the hypothesis that pressure antagonizes ethanol by acting on putative ethanol 'binding pockets."""""""" Phase 2 will test the hypothesis that pressure antagonizes ethanol by acting on specific amino acids or regions within TM21TM3 of glycine, GABAA and/or GABAP receptors.
Specific Aim 2, will develop molecular models for the site(s) and mechanism(s) of pressure antagonism of ethanol.
This aim will be accomplished using methods developed by our collaborators to model ethanol's sites of action in LGICS. We will apply this strategy using data from Aim 1 results to model pressures site(s) and mechanism(s) of action in these receptors. Models like those to be generated from Aim 2 will be used in future proposals to design pharmacological agents that can mimic pressure's action on molecular targets mediating alcohol antagonism. These agents can form the bases of novel prevention and treatment strategies for alcoholism and alcohol abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA013890-01
Application #
6556258
Study Section
Special Emphasis Panel (ZAA1-CC (15))
Program Officer
Twombly, Dennis
Project Start
2003-05-01
Project End
2006-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
1
Fiscal Year
2003
Total Cost
$162,500
Indirect Cost
Name
University of Southern California
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Crawford, Daniel K; Trudell, James R; Bertaccini, Edward J et al. (2007) Evidence that ethanol acts on a target in Loop 2 of the extracellular domain of alpha1 glycine receptors. J Neurochem 102:2097-109

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