Alcohol and nicotine are frequently used together. An extremely large fraction of alcoholics are also heavy smokers and studies in rodents have demonstrated that mice and rats selectively bred for differences in initial sensitivity to ethanol also differ in response to nicotine. The pharmacological and behavioral effects of ethanol and nicotine are both complex. Ethanol has multiple sites of actions in the brain including many ligand-gated ion channels. Nicotine?s actions in the brain are produced by the activation of nicotinic cholinergic receptors that are multimeric ion channels encoded by a large gene family. The goal of the proposed studies is to determine whether any of the nicotinic receptor subunits are involved in specific actions of alcohol by creating and testing null mutants with deletions in several of the important nicotinic receptor genes. Studies will investigate single-gene manipulations in the major, widely expressed subunits as well as other subunits with more limited but interesting expression patterns. A wide range of pharmacological and behavioral actions of ethanol will be assessed including: initial sensitivity, several forms of tolerance, anxiety, learning and memory, attention, ethanol consumption and impulsivity.
The specific aims are: 1.) To examine the role of alpha4 containing brain nicotinic receptors in mediation of alcohol?s effects by creating constitutive and conditional alpha4 null mutants as well as those containing a site specific mutation in the alpha4 gene; 2.) To determine whether an alpha7 brain nicotinic receptor null mutation alters ethanol-related behaviors; and 3.) To examine the effects of alpha4 and alpha7 receptor null mutations on various genetic backgrounds. The results of these studies should provide a better understanding of the potential interactions and mechanisms underlying the co-administration of ethanol with nicotine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013018-04
Application #
6881433
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Neuhold, Lisa
Project Start
2002-05-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$420,336
Indirect Cost
Name
University of Colorado at Boulder
Department
Genetics
Type
Other Domestic Higher Education
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
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Keller, Jason J; Keller, Ashleigh B; Bowers, Barbara J et al. (2005) Performance of alpha7 nicotinic receptor null mutants is impaired in appetitive learning measured in a signaled nose poke task. Behav Brain Res 162:143-52
Bowers, Barbara J; McClure-Begley, Tristan D; Keller, Jason J et al. (2005) Deletion of the alpha7 nicotinic receptor subunit gene results in increased sensitivity to several behavioral effects produced by alcohol. Alcohol Clin Exp Res 29:295-302
Wehner, J M; Keller, J J; Keller, A B et al. (2004) Role of neuronal nicotinic receptors in the effects of nicotine and ethanol on contextual fear conditioning. Neuroscience 129:11-24

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