Behavioral sensitivity to ethanol is a complex trait that appears to depend upon a number of different genes that all contribute to the behavioral phenotype. We will use electrophysiological techniques to study the actions of ethanol at the cellular level in animals that have been selected on the basis of behavioral responses to ethanol, in order to identify the cellular bases for differences in behavior. One mechanism that we hypothesize is an important determinant of behavioral ethanol sensitivity is the acute neuronal tolerance that we observe in electro- physiological experiments, which is maximal within 5-7 minutes following methanol application, and occurs rapidly enough that this type of tolerance could occur even before blood ethanol concentrations have reached their peak levels. We have observed this form of tolerance at the single cell level in animals selectively bred for ethanol sensitivity (short sleep mice and low alcohol sensitivity rats), but not in animals selected for increased ethanol sensitivity (long sleep mice and high alcohol sensitivity rats). We propose to compare this very rapid phase of tolerance between brain regions (hippocampus and cerebellum), and in other lines of mice that have been selected specifically for the rapid acquisition of behavioral ethanol tolerance. We also propose to determine whether there are cellular mechanisms that can account for the behavioral phenomenon of acute functional tolerance, which develops more slowly ( greater than 30 minutes), and for which no electrophysiological correlates have been identified. A second series of experiments will examine congenic mice that isolate individual quantitative trait loci (QTLs) for behavioral sensitivity to ethanol on a ethanol insensitive short sleep or ethanol sensitive long sleep background. We hypothesize that some of the QTLs will be associated with differences that we have previously observed in electrophysiological responses to ethanol in hippocampus and cerebellum. We will determine whether the same QTL-associated genes control initial ethanol sensitivity in the cerebellum and in the hippocampus, and whether there are separate and distinct QTLs associated with differences in acute neuronal tolerance and initial sensitivity. A final set of experiments will examine differences in GABAergic responses at the cellular level in lines of transgenic mice that overexpress either the gamma2L or gamma2S subunit of the GABAa receptor, which has been hypothesized to play a role in the ethanol sensitivity of this receptor.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
5P50AA003527-25
Application #
6563132
Study Section
Project Start
2001-12-01
Project End
2002-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
25
Fiscal Year
2002
Total Cost
$184,557
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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

Showing the most recent 10 out of 355 publications