Alcohol abuse is a major social and economic problem for which current drug treatments are inadequate. A primary difficulty with the development of novel treatments for alcoholism is that the molecular nature of the interaction of the nervous system with the drug is incompletely understood. Alcohol is a small, easily diffusible molecule that probably interacts with many proteins in all neurons. A significant challenge for researchers is to determine which interactions are important for altering nervous system function and, ultimately, for the development of addiction. The nervous system mounts a dynamic response to exposure to alcohol that consists of several levels of the development of tolerance. The development of tolerance is important in the etiology of addiction. Variation in the ability to develop tolerance is an important component of the genetic diversity that predicts an individualb"s propensity to abuse alcohol. We study the molecular mechanics of acute tolerance to ethanol, which develops during a single ethanol exposure. In mammals, this is observed as a recovery of coordination and cognitive ability at a blood ethanol level that is higher than the level that intoxicated the animal initially. In Caenorhabditis elegans (C. elegans), we observe acute tolerance as a recovery of coordinated locomotion during a single exposure to a constant dose of ethanol. C. elegans is an excellent model for the study of neural function because its extremely simple and well-characterized nervous system (302 neurons) contains at least 118 different neuronal cell types and uses many of the same neurotransmitters as are used by the mammalian brain. C. elegans genetics provides a facile means of dissecting nervous system function, and can be used effectively to address questions of drug effects on neurons. This project is designed to determine the molecular mechanisms of the development of acute tolerance. We will take a forward genetics approach by genetically screening for mutations that disrupt the development of acute tolerance to ethanol.
The specific aims of this proposal are: 1- Genetically screen for mutations that disrupt development of acute tolerance to ethanol. 2- Molecularly characterize several of the mutations isolated in the genetic screen. 3- Characterize the function of the genes identified in Specific Aim 2 in acute tolerance. Together, the specific aims of this proposal are designed to thoroughly examine the molecular mechanisms of development of AFT.

Public Health Relevance

The project aims to use a forward genetic screen to identify genes in the nematode C. elegans that are required for the development of acute tolerance to ethanol. If the discovered genes are related to human genes then variation in those genes or in genes that regulate their activity or expression is likely to impact on an individual's initial response to alcohol and therefore could predispose that individual to alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016837-05
Application #
8242833
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Reilly, Matthew
Project Start
2008-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$245,564
Indirect Cost
$74,278
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Chan, Robin F; Lewellyn, Lara; DeLoyht, Jacqueline M et al. (2014) Contrasting influences of Drosophila white/mini-white on ethanol sensitivity in two different behavioral assays. Alcohol Clin Exp Res 38:1582-93
Raabe, Richard C; Mathies, Laura D; Davies, Andrew G et al. (2014) The omega-3 fatty acid eicosapentaenoic acid is required for normal alcohol response behaviors in C. elegans. PLoS One 9:e105999
Zhang, Zhe; Tang, Qiong-Yao; Alaimo, Joseph T et al. (2013) SLO-2 isoforms with unique Ca(2+) - and voltage-dependence characteristics confer sensitivity to hypoxia in C. elegans. Channels (Austin) 7:194-205