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

Aaron Janowsky, Clifford Mah, Robert A. Johnson, Christopher L. Cunningham, Tamara J. Phillips, John C. Crabbe, Amy J. Eshleman, John K. Belknap

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Binding of 3β-(4-iodophenyl) tropane-2β-carboxylic acid methyl ester ([125]RTI-55) to the dopamine transporter (DAT) in neostriatum from C57BL/6J, DBA/2J, and 21 BXD recombinant inbred (RI) mouse strains indicated highly significant strain differences in DAT density (Bmax) but no significant differences in affinity (Kd) for this radioligand. Strain mean Bmax values and the known genomic locations of 1390 marker loci were used to carry out a genome-wide search for quantitative trait loci (QTLs), which are chromosomal sites containing genes that influence DAT expression. This search revealed an unusually large effect QTL on chromosome 19 in the region of the pro-opiomelanocortin pseudogene Pomc-ps1 (8-11 cM), homologous to regions of human chromosomes 9q21 and 11q12-13. This QTL (logarithm of the odds 4.7, df = 1, p = 3 × 10-6) by conservative estimates accounts for just over 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- or hyperthermia), but were not correlated with behaviors related to sensitization, reward, voluntary consumption, stereotypy, or seizures induced by these two psychostimulant drugs. The results suggest that there is a gene(s) on proximal chromosome 19 that strongly influences DAT expression in neostriatum and may influence psychostimulant-induced activity and thermal responses.

Original languageEnglish (US)
Pages (from-to)634-643
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume298
Issue number2
StatePublished - Aug 2 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'Mapping genes that regulate density of dopamine transporters and correlated behaviors in recombinant inbred mice'. Together they form a unique fingerprint.

  • Cite this