Saturday, June 14, 2025
6/14/2025
MODULATION OF CHRONIC ALCOHOL EFFECTS BY A NICOTINIC RECEPTOR POLYMORPHISM - DESCRIPTION (provided by applicant): The public health relevance of this project is that science does not understand alcoholism, nicotine addiction or the strong interaction between the two, and these circumstances decrease our ability to treat these addictions. One reason that we do not understand alcoholism and its association with nicotine addiction is that few experimental models mimic an alcoholic's behavior. Our long term goal is to build preclinical foundations for developing novel therapies for alcoholism. In accordance with this goal, we have developed a chronic ethanol exposure treatment that attempts to imitate an alcoholic's bingeing on alcohol and avoidance of alcohol withdrawal. The objective of this application is to characterize the potential interaction of the major nicotine binding site in brain with the effects of chronic ethanol exposure in a mouse model. Previous studies using acute exposure paradigms strongly suggest that a small mutation in a major nicotinic receptor subunit (a4) changes the receptor's sensitivity to ethanol and nicotine. Our central hypothesis is that the a4 mutation influences the chronic effects of ethanol by modulating the sensitivity of nicotinic receptors to ethanol, thus altering downstream mechanisms that contribute to addiction-related behavior. This project will test whether the nicotinic receptor mutation alters the effects of chronic ethanol exposure by using mice that express different forms of the mutation. Experiments proposed in our first specific aim will treat mice chronically with ethanol and assess the effects of the treatments and of the nicotinic receptor mutation on nicotine consumption, nicotine preference and ethanol withdrawal. Our second specific aim also involves the chronic treatment of mice with ethanol. However, these experiments will determine the effects of the treatments and of the mutation on nicotinic receptor-mediated release of a major inhibitory neurotransmitter (?-aminobutyric acid; GABA). We expect that variability in some of the phenotypes described above will be associated with the nicotinic receptor mutation. If the data indicate that our hypothesis is correct, then our mouse model could eventually be used to test new drugs for alcoholism or nicotine addiction that are targeted at a4-containing nicotinic receptors. Thus, this research project is consistent with the NIAAA's mission of supporting research in genetics, neuroscience, and treatments for alcoholism. In addition, funding of this small, focused R15 project will enhance the research capabilities of our institution, expose more of our medical students to research, and increase the awareness of future physicians towards important aspects of alcoholism and its potential treatment. The public health relevance of this project is that science does not understand alcoholism, nicotine addiction or the strong interaction between the two, and these circumstances decrease our ability to treat these addictions. We have developed a mouse model of genetic predisposition to alcoholic- and tobacco addiction- related behavior, and this model will be used in the proposed experiments that attempt to imitate an alcoholic's bingeing on alcohol and avoidance of alcohol withdrawal. If our mouse model is relevant under these chronic alcohol treatment conditions, we expect that the model could eventually be used to test new drugs for alcoholism or nicotine addiction that are targeted towards the receptor proteins that mediate nicotine's action and are affected by ethanol.
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