LOCALIZATION OF GENES MEDIATING ACUTE AND SENSITIZED LOCOMOTOR RESPONSES TO COCAINE IN BXD TY RECOMBINANT INBRED MICE/

Sensitization to the psychostimulant effects of cocaine has received w idespread attention because concomitant changes occur in neurochemical pathways that are part of the brain reward pathway. The current study was undertaken with the purpose of mapping genes determining sensitiv ity to the acute stimulant and sensitizing effects of cocaine. Sensiti vity and sensitization to cocaine (5, 10, and 40 mg/kg) were measured in 25 BXD/Ty recombinant inbred (BXD RI) strains and the progenitor C5 7BL/6J (B6) and DBA/2J (D2) strains. Quantitative trait locus (QTL) ma pping provisionally localized cocaine sensitivity genes to regions on all chromosomes except 6, 11, 17, and X; sensitization QTLs were local ized to chromosomes 1-10, 13, 15, 18, 19, and X. Provisional QTLs for locomotion after saline injection in a novel setting were mapped to ch romosomes 1, 3-6, 9, 12, 13, 18, and 19 and in a familiar setting to c hromosomes 4-7, 9, 13, and 19. There were both common and unique QTL r egions across the phenotypes. Evidence for a genetic association betwe en magnitude of acute cocaine response and sensitization was obtained for only the 10 mg/kg dose. Some common QTL regions for cocaine, ethan ol, and methamphetamine responses suggest the possibility that these d rugs induce stimulant effects or sensitization through some common mec hanisms. However, independent mechanisms were also indicated. Many can didate genes reside near the provisional QTLs mapped for cocaine respo nses, including genes coding a variety of neurotransmitter and hormone receptors. These data, once confirmed, should prove useful for direct ing investigations of acute and chronic cocaine effects down already s uspected and novel avenues.