This exploratory grant application represents the effort of a researcher that is new to the ethanol field. The 3 proposed experiments provide an opportunity to explore in mice, excessive ethanol consumption elicited in the schedule-induced polydipsia (SIP) paradigm. As the SIP paradigm has rarely been used to elicit excessive ethanol drinking in mice, experiment I will provide task validation by systematically testing male mice from the BxD, RI strains along with their parental strains. Once excessive ethanol consumption develops in some of these BXD RJ strains, additional ethanol concentrations will be tested in order to establish dose response relationships in these mice. Variability in the amount of ethanol drinking in the BxD RI lines will permit an initial QTL analysis of potential genetic loci involved in this behavior. Experiment 2 will use mice obtained from an NIH supported neuromutagenesis program (UOI: Targeted Mutagenesis of the Mouse Genome and Neural Phenotypes). In this experiment, mutant pedigrees that respond extremely in the ethanol 2-bottle choice test will be rebred and then tested in the SIP ethanol paradigm. Results of this experiment will provide convergent evidence of genetic loci associated with susceptibility to excessive ethanol drinking. In experiment 3, microarray technology will be used to more precisely identify candidate genes whose expression is correlated with excessive, voluntary ethanol drinking in the SIP paradigm.
The specific aims are: (1) to establish the SIP paradigm as a reasonable way of inducing consistent and excessive ethanol consumption in mice and (2) to characterize using QTL, mutant mice and microarray analyses the genetic differences correlated with excessive and heritable ethanol drinking in this paradigm.
