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.
