DIFFERENTIAL COCAINE SENSITIVITY BETWEEN 2 CLOSELY-RELATED SUBSTRAINSOF C57BL-MICE

While there is evidence that individual differences in response to coc aine are mediated, in part, by genetic factors, no single gene has bee n identified that can account for differential responsivity to cocaine . Recent studies in our laboratory may have moved us closer to identif ication of the gene(s) underlying cocaine sensitivity. We have identif ied several cocaine-related phenotypes on which two substrains of C57B L mice (6J and ByJ) differ. The genealogy of these two substrains lead s to the expectation that they should be genetically very similar, dif fering at only a few loci. The large differences between the two subst rains in cocaine sensitivity may be influenced by allelic differences at a major gene mediating the actions of cocaine. Naive ByJ mice are m ore resistant to cocaine-induced seizures than are 6J mice. Furthermor e, among 6J mice repeated exposure to cocaine results in a decreased s usceptibility to cocaine-induced seizure, while among ByJ mice, the sa me treatment gives rise to an increased susceptibility to seizures. In contrast to their lower sensitivity to cocaine-induced seizures, ByJ mice show a greater sensitivity to cocaine's locomotor stimulant effec ts. Furthermore, the repeated pairing of cocaine and the test environm ent results in the development of conditioned locomotion during subseq uent exposure to that environment among 6J, but not ByJ, mice. Similar ly, a greater degree of conditioned sensitization to the locomotor sti mulant effects of cocaine develops in 6J mice.