Alcohol and nicotine dependence commonly co-occur and a variety of research suggests some of this co-morbidity may be due to overlapping genetic factors. Converging evidence from electrophysiology studies and rodent models of alcohol- and tobacco-related phenotypes supports the hypothesis that neuronal nicotinic receptors (nAChRs) may be a common site of action for these drugs. The nAChRs are ligand-gated ion channels containing a central cation pore that act as the primary targets for nicotine and the endogenous agonist acytelcholine. Alcohol appears to play a role in modulating the pharmacological properties of nicotine binding at nAChRs, usually by enhancing receptor function. Furthermore, several nicotinic receptor subtypes are known to be present on dopaminergic neurons and involved in mediating the release of dopamine in response to alcohol and nicotine. Through this mesolimbic dopaminergic pathway, these receptors (including the 13-7 and 22-4 subunits) may contribute to the rewarding properties associated with substance use. Recent work has provided evidence that several of the human nAChR subunit genes are associated with alcohol and nicotine behaviors in humans, including age of initiation, early subjective response, and dependence. This proposal will extend these human studies in three ways. First, the human genes for the 13-6 and 22-4 nAChR subunits will be resequenced using DNA samples from 100 individuals to identify novel variations. Second, multiple variations in these genes will be characterized in a sample of 4,146 individuals, for which DNA and alcohol and nicotine behavioral data have already been collected, to test for associations between specific DNA variations and these behaviors. Third, laboratory-based methods will be conducted to determine whether specific variations lead differences in gene expression using cell culture assays.

Public Health Relevance

Results from each of these aims will facilitate a better understanding of how naturally occurring variations in these genes might contribute to the underlying molecular mechanisms responsible for differences in alcohol and nicotine behaviors. Such knowledge should lead to the development of improved prevention and treatment of individuals who suffer from these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA017889-05
Application #
8468086
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Parsian, Abbas
Project Start
2009-09-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$374,671
Indirect Cost
$125,066
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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Flora, Amber V; Zambrano, Cristian A; Gallego, Xavier et al. (2013) Functional characterization of SNPs in CHRNA3/B4 intergenic region associated with drug behaviors. Brain Res 1529:1-15

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