Mapping genes that regulate density of dopamine transporters and correlated behaviors in recombinant inbred mice

Binding of 3 beta-(4-iodophenyl) tropane-2 beta -carboxylic acid methyl est er ([I-125]RTI-55) to the dopamine transporter (DAT) in neostriatum from C5 7BL/6J, DBA/2J, and 21 BXD recombinant inbred (RI) mouse strains indicated highly significant strain differences in DAT density (B-max) but no signifi cant differences in affinity (K-d) for this radioligand. Strain mean B-max values and the known genomic locations of 1390 marker loci were used to car ry out a genome-wide search for quantitative trait loci (QTLs), which are c hromosomal sites containing genes that influence DAT expression. This searc h revealed an unusually large effect QTL on chromosome 19 in the region of the proopiomelanocortin pseudogene Pomc-ps1 (8-11 cM), homologous to region s of human chromosomes 9q21 and 11q12-13. This QTL (logarithm of the odds 4 .7, df = 1, p = 3 x 10(-6)) by conservative estimates accounts for just ove r half of the genetic variation in DAT binding site density. The QTL is not the DAT gene itself (Dat1, chromosome 13), but a powerful modulator of DAT expression in neostriatum. Furthermore, DAT expression levels in 20 of the BXD RI strains and the chromosome 19 QTL were correlated with cocaine and methamphetamine-induced locomotor activation and thermic responses (hypo- o r hyperthermia), but were not correlated with behaviors related to sensitiz ation, reward, voluntary consumption, stereotypy, or seizures induced by th ese two psychostimulant drugs. The results suggest that there is a gene(s) on proximal chromosome 19 that strongly influences DAT expression in neostr iatum and may influence psychostimulant-induced activity and thermal respon ses.