QUANTITATIVE TRAIT LOCI AFFECTING METHAMPHETAMINE RESPONSES IN BXD RECOMBINANT INBRED MOUSE STRAINS

Individual differences in most behavioral and pharmacological response s to abused drugs are dependent on both genetic and environmental fact ors. The genetic influences on the complex phenotypes related to drug abuse have been difficult to study using classical genetic analyses. Q uantitative trait locus (QTL) mapping is a method that has been used s uccessfully to examine genetic contributions to some of these traits b y correlating allelic variation in polymorphic genetic markers of know n chromosomal location with variation in drug-response phenotypes. We evaluated several behavioral responses to multiple doses of methamphet amine (METH) in C57BL/6J (B6), DBA/2J (D2), and 25 of their recombinan t inbred (BXD RI) strains. Stereotyped chewing, horizontal home cage a ctivity, and changes in body temperature after 0, 4, 8, or 16 mg/kg ME TM, as well as stereotyped climbing behavior after 16 mg/kg METH, were examined. Associations (p < 0.01) between METH sensitivity and alleli c status at multiple microsatellite genetic markers were subsequently determined for each response. QTLs were provisionally identified for e ach phenotype, some unique to a particular behavior and others that ap peared to influence multiple phenotypes. Candidate genes suggested by these analyses included several that mapped near genes relevant for th e neurotransmitters acetylcholine and glutamate. The locations of QTLs provisionally identified by this analysis were compared with QTLs hyp othesized in other studies to influence methamphetamine- and cocaine-r elated phenotypes. In several instances, QTLs appeared to overlap, whi ch is consistent with idea that common neural substrates underlie some responses to psychostimulants.