Unequivocal identification of Quantitative Trait Loci (QTLs) that affect behavioral traits has been difficult, with progress limited by the behavioral and genetic complexity of these phenotypes. To circumvent complicating factors such as the effects of more than one gene, genetic interaction, etc., our strategy is to take advantage of a new genetic analytical approach, the use of congenic Recombinant Quantitative-Trait- Loci Introgression (RQI) strains, developed in our laboratory by repeated backcross-intercross cycles with concomitant selection for mesencephalic tyrosine hydroxylase activity (TH/MES, an index of number of dopamine neurons) for the genetic dissection of the murine mesotelencephalic dopamine system. We will focus on alcohol preference and alcohol-induced dopamine release in the nucleus accumbens because dopamine has been implicated in the mechanisms of alcohol-related behaviors in rodents and our preliminary results indicated significant differences both in brain dopamine systems and in alcohol preference in the progenitor and RQI strains. The overall goal of the proposal is to map and clone genes that play a pivotal role in alcohol preference. Once the QTLs are mapped and the congenic RQI strains that carry alcohol preference-QTLs are identified, a further goal of the proposal is to study the mechanism of QTL-action on a homogeneous genetic background provided by the congenic RQI lines. Identification of human homolog genes offers the potential for prevention and treatment of alcohol abuse.
Our specific aim i s (a) to map alcohol preference QTLs in sets of congenic Recombinant Quantitative- Trait-Loci introgression strains by analyzing the distribution and polymorphic microsatellite markers in the strains and investigating correlations between the markers and alcohol preference measured in a limited access paradigm, and (b) to investigate the effect of alcohol on nucleus accumbens dopamine function by in vivo microdialysis in congenic RQI strains with genetically determined high, intermediate and low alcohol preference.
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