Core - Scientific/Selection for Alcohol-Related Phenotypes

Erwin, V Gene

Abstract

In animals a convincing body of literature has shown genetic influences on ethanol-related behaviors including measures of initial sensitivity, voluntary ethanol consumption (VEC), acute functional tolerance (AFT) and withdrawal severity (WS) following chronic ethanol exposure. The proposed studies will identify those genes and/or expression products which mediate genetic differences in VEC, AFT, and WS. Selective breeding procedures will be used to obtain ethanol-avoiding congenic strains of ethanol-preferring C57BL mice. Investigators will use these mice and RFLP and PCR methods to determine quantitative trait loci (QTL) for VEC and correlated behavioral effects of ethanol including locomotor activation and inhibition, and conditioned place-preference. Two other studies will obtain, by selective breeding from a genetically heterogeneous (HS) stock, replicate lines of mice which differ in AFT (HAFT1,2 and LAFT1,2) and in WS (HW1,2 and LW1,2). Specific neurochemical hypotheses for GABAergic, dopaminergic, serotonergic, and peptidergic mediation of these alcohol-related behaviors will be investigated. Identification of the genes and subsequent neuronal and neurochemical processes mediating individual differences in VEC, AFT, and WS will lead ultimately to improved methods of identifying individuals at risk for alcoholism and consequently will enhance methods of prevention and treatment of this major societal problem.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Type: Specialized Center (P50)
• Project #: 5P50AA003527-19
• Application #: 5204207
• Support Year: 19
• Fiscal Year: 1996

Publications

Bennett, B; Carosone-Link, P; Beeson, M et al. (2008) Genetic dissection of quantitative trait locus for ethanol sensitivity in long- and short-sleep mice. Genes Brain Behav 7:659-68

Vasiliou, Vasilis; Ziegler, Thomas L; Bludeau, Pequita et al. (2006) CYP2E1 and catalase influence ethanol sensitivity in the central nervous system. Pharmacogenet Genomics 16:51-8

Bowers, Barbara J; Miyamoto-Ditmon, Jill; Wehner, Jeanne M (2006) Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cgamma. Pharmacol Biochem Behav 85:441-7

Zimatkin, Sergey M; Pronko, Sergey P; Vasiliou, Vasilis et al. (2006) Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res 30:1500-5

Radcliffe, Richard A; Bludeau, Pequita; Asperi, William et al. (2006) Confirmation of quantitative trait loci for ethanol sensitivity and neurotensin receptor density in crosses derived from the inbred high and low alcohol sensitive selectively bred rat lines. Psychopharmacology (Berl) 188:343-54

Smith, Amy M; Bowers, Barbara J; Radcliffe, Richard A et al. (2006) Microarray analysis of the effects of a gamma-protein kinase C null mutation on gene expression in striatum: a role for transthyretin in mutant phenotypes. Behav Genet 36:869-81

Bowers, Barbara J; Radcliffe, Richard A; Smith, Amy M et al. (2006) Microarray analysis identifies cerebellar genes sensitive to chronic ethanol treatment in PKCgamma mice. Alcohol 40:19-33

Haughey, Heather M; Kaiser, Alan L; Johnson, Thomas E et al. (2005) Norepinephrine transporter: a candidate gene for initial ethanol sensitivity in inbred long-sleep and short-sleep mice. Alcohol Clin Exp Res 29:1759-68

Wu, Peter H; Poelchen, Wolfgang; Proctor, William R (2005) Differential GABAB Receptor Modulation of Ethanol Effects on GABA(A) synaptic activity in hippocampal CA1 neurons. J Pharmacol Exp Ther 312:1082-9

Quertemont, Etienne; Eriksson, C J Peter; Zimatkin, Sergey M et al. (2005) Is ethanol a pro-drug? Acetaldehyde contribution to brain ethanol effects. Alcohol Clin Exp Res 29:1514-21