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.
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.
|Melroy, Whitney E; Stephens, Sarah H; Sakai, Joseph T et al. (2014) Examination of genetic variation in GABRA2 with conduct disorder and alcohol abuse and dependence in a longitudinal study. Behav Genet 44:356-67|
|Darlington, Todd M; McCarthy, Riley D; Cox, Ryan J et al. (2014) Mesolimbic transcriptional response to hedonic substitution of voluntary exercise and voluntary ethanol consumption. Behav Brain Res 259:313-20|
|Kamens, H M; Corley, R P; McQueen, M B et al. (2013) Nominal association with CHRNA4 variants and nicotine dependence. Genes Brain Behav 12:297-304|
|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|
|Gallego, Xavier; Cox, Ryan J; Laughlin, James R et al. (2013) Alternative CHRNB4 3'-UTRs mediate the allelic effects of SNP rs1948 on gene expression. PLoS One 8:e63699|
|Darlington, T M; Ehringer, M A; Larson, C et al. (2013) Transcriptome analysis of Inbred Long Sleep and Inbred Short Sleep mice. Genes Brain Behav 12:263-74|
|Stephens, Sarah H; Hoft, Nicole R; Schlaepfer, Isabel R et al. (2012) Externalizing behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster. Behav Genet 42:402-14|
|Haberstick, Brett C; Ehringer, Marissa A; Lessem, Jeffrey M et al. (2011) Dizziness and the genetic influences on subjective experiences to initial cigarette use. Addiction 106:391-9|
|Hoft, N R; Stitzel, J A; Hutchison, K E et al. (2011) CHRNB2 promoter region: association with subjective effects to nicotine and gene expression differences. Genes Brain Behav 10:176-85|
|Ehringer, Marissa A; McQueen, Matthew B; Hoft, Nicole R et al. (2010) Association of CHRN genes with "dizziness" to tobacco. Am J Med Genet B Neuropsychiatr Genet 153B:600-9|
Showing the most recent 10 out of 11 publications