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 abuse potential 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 general goals. The first is the use of detailed breeding studies to continue our genetic characterization of the activational effect. Our work has suggested that a simple genetic system with as few as three genes might influence this character, and several breeding designs will further test this hypothesis. The second 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, and neurobiological foundations of ethanol's activating actions, and provide a strong tool for mapping and molecular biological study. A third goal involves characterizing the psychopharmacological phenomenology of the paradoxical activational effect of ethanol. We are attempting to define the range of behaviors, such as aggressive behavior, which are commonly genetically influenced in the domain of these activational effects of ethanol.
