One of the hallmarks of alcohol's many actions is it's frequent biphasic effect. Low doses often produce activation of behavioral and physiological characters. The behavioral activation is variously described as a stimulant effect, euphoria, and disinhibition. Although clear resolution of its dimensions is not yet available, such activating effects are now receiving focus in some genetically based theories of alcoholism. In Cloninger's scheme of alcoholic subtypes, Type II is argued to use alcohol for these euphoriant effects, implying a genetically based sensitivity to this domain of ethanol action. A general working hypothesis states that these activational effects are somehow related to the reinforcing properties of ethanol, and therefore represent an important addiction liability. A small literature on neurobiological aspects of the activation effect implicate-brain dopamine systems, one neurotransmitter known to be important in brain reward systems. Laboratory studies of behavioral activation by ethanol have shown clear genetic influences on this type of initial sensitivity. Mouse locomotor activity has been the most highly investigated phenotype for this question of ethanol activation. The studies outlined here have three goals. The first is the use of genetically defined mouse strains and selected lines to identify any relationships between the simple locomotor activating effects of ethanol and its anxiolytic effects, and also with its potential aggression-stimulating properties, relationships important for evaluation of some of the current theories of alcoholism subtypes. The second goal is the use of detailed breeding studies to genetically characterize the activational effect. On the basis of several tentative lines of evidence, there is reason to suspect a major gene effect (i.e. single-locus), and classical Mendelian cross designs will test this hypothesis. The third goal is the production of congenic strains of mice where the genetic alleles producing activation in three different stocks, are backcrossed onto the background of the C57Bl/6 strain which shows no ethanol-induced activation. Congenic strains are an extremely powerful technique, not heretofore used in alcohol research. They will, in the future, permit tests of specific hypotheses concerning the behavioral, neurobiological, and molecular genetic foundations of ethanol's activating actions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA009038-03
Application #
3113168
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1991-08-01
Project End
1994-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
State University of New York at Albany
Department
Type
Schools of Arts and Sciences
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12222
Downing, C; Rodd-Henricks, K K; Flaherty, L et al. (2003) Genetic analysis of the psychomotor stimulant effect of ethanol. Genes Brain Behav 2:140-51
Downing, Chris; Rodd-Henricks, Kristina; Marley, Rodney J et al. (2003) Genetic variation in the psychomotor stimulant properties of cocaine in Mus musculus. Psychopharmacology (Berl) 167:159-66
Caldarone, B; Saavedra, C; Tartaglia, K et al. (1997) Quantitative trait loci analysis affecting contextual conditioning in mice. Nat Genet 17:335-7
Dudek, B C; Tritto, T (1995) Classical and neoclassical approaches to the genetic analysis of alcohol-related phenotypes. Alcohol Clin Exp Res 19:802-10
Tritto, T; Dudek, B C (1994) Differential activating effects of ethanol in C57BL/6Abg and DBA/2Abg mice. Alcohol 11:133-9
Dudek, B C; Tritto, T; Underwood, K A (1994) Genetic influences on locomotor activating effects of ethanol and sodium pentobarbital. Pharmacol Biochem Behav 48:593-600
Dudek, B C; Tritto, T (1994) Biometrical genetic analysis of ethanol's psychomotor stimulant effect. Alcohol Clin Exp Res 18:956-63
Dudek, B C; Underwood, K A (1993) Selective breeding, congenic strains, and other classical genetic approaches to the analysis of alcohol-related polygenic pleiotropisms. Behav Genet 23:179-89
Dudek, B C; Yi, D K; Gilliam, D M et al. (1993) Comparisons of subcolonies of selectively bred long-sleep and short-sleep mice. Behav Genet 23:245-50