Extensive preliminary data demonstrate genetic influences on behavioral responses to cocaine (COC) and methamphetamine (MA) in C57Bl/6J (B6), DBA/2J (D2) and 25 of their recombinant inbred (BXD Rl) strains of mice. The responses studied include several related to high-dose toxicity (e.g. MA stereotyped chewing, climbing, exophthalmos, and temperature changes; COC seizures) and low-dose locomotor activition/sensitization responses to COC and MA. Using quantitative trait locus (QTL) mapping methods, we have provisionally identified the location of multiple QTLs for each drug response in the mouse genome. A quantitative trait locus (QTL) is a chromosome site containing gene or genes which appear to influence these responses to psychostimulants. The statistical approach we employ requires that the provisional QTLs we have identified must be further tested in additional populations before linkage in the proposed chromosomal regions can be accepted. The proposed studies will rigorously assess the strength of the provisional genetic mapping assignments by examining F2 individuals from the cross of B6 and D2 progenitors, and lines selectively bred from the F2 population to differ in drug response. In each of these populations, allele frequencies for the associated markers should cosegregate in individual mice with differences in magnitude of the drug response mapped. For those QTLs rigorously verified, congenic strains will be developed by backcrossing the relevant chromosomal region onto a progenitor B6 or D2 strain. These congenic strains will provide a powerful genetic animal model for future mechanism-oriented tests of candidate gene function. Where a candidate gene is not obvious, the congenics will also facilitate location of the relevant gene through positional cloning. Because of the high degree of similarity (synteny) between the mouse and human genomes, identification of the location of specific genes in mice will allow rapid identification of their human counterparts. The proposed studies build on 5 years of previous work and represent progress toward the identification of specific genes underlying susceptibility to aspects of psychostimulant toxicity and activation/sensitization.
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