Bruce C. Dudek - US grants

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.

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.

The current research on one of the hallmarks of alcohol's many actions, 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 dimensions is not yet available, such activating effects are now receiving focus in some genetically based theories of alcoholism, such as 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. 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. Data collected have already provided a convincing picture of the genetic control as a simple genetic system of a small polygenic size. Three congenic strains are being developed to facilitate studies of psychopharmacological, physiological, neurochemical, molecular genetic and other phenomenological aspects of ethanol's paradoxical low-dose stimulant-like effect. These congenic strains are three pairs of inbred strains which differ from the pair member at only those genes which control the behavioral activation phenotype (as well as a small amount of tightly linked DNA). The successful completion of their development, at generation 12, will produce tools with considerable value in studies of biological pleiotropisms of these genes, their physiological/biochemical functioning, and their molecular genetic location and identity. The coherence sensitivity to ethanol, its activational effects.

While there is a substantial body of evidence that individual differences in response to cocaine are mediated, in part, by genetic factors, no single gene has been identified that can account for differential responsivity to cocaine. Recent studies in our laboratory may have moved us closer to the identification of the gene(s) underlying a number of cocaine's actions. We have identified several cocaine-related phenotypes on which 2 closely related substrains of C57BL mice (6J and 6ByJ) differ substantially. Among these are cocaine-induced locomoting and cocaine-induced seizures. The genealogy of these 2 substrains leads to the expectation that they should be genetically very similar, differing at only a few genetic loci. Thus, the large differences between the 2 substrains in cocaine responsivity probably are mediated by allelic differences for a single gene mediating cocaine's effects. As a first step towards identifying the gene(s) underlying cocaine-related phenotypes, we are proposing to conduct a series of genetic manipulaitons to further characterize the genetic architecture underlying the differences between the 2 substrains in cocaine sensitivity. We propose to conduct full buomerical analyses cocaine-induced locomoting and seizures using classical mendelian breeding strategies to determine the mode of inheritance of each behavior, estimate the number of genes mediating each phenotype and determine if the phenotypes are mediated by the same gene(s). We also propose to conduct an abbreviated from of a congenic breeding strategy to transfer the differential alleles underlying these 2 phenotypes onto the genetic backgrounds of the 2 substrains. This will allow us to further assess whether these behaviors are mediated by a single gene. These studies will provide a model for the furture production of congenic lines of mice segregating only at the genetic loci mediating cocaine sensitivity. We are also proposing to screen a battery of substrains related to the 3 strains of mice being used for RI-QTL mapping studies (C57, DBA & A) on these two cocaine-related phenotypes. These 3 studies will facilitate furture mapping of the gene(s) underlying cocaine's behavioral effects. Finally, we are planning to characterize any possible cocaine pharmacokinetic differences between the 2 strains that could account for their differential sensitivity to the drug. We also propose to characterize 2 neurotransmitter systems (glutamatergic and dopaminergic) in brain regions known to be associated with some of cocaine's pharmacological effects in the 6J and BhJ strains. These studies will contribute to the identification of risk factors for cocaine addiction and the development of preventative and therapeutic intervention strategies.