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Research ArticleNEUROPHARMACOLOGY

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 and John K. Belknap
Journal of Pharmacology and Experimental Therapeutics August 2001, 298 (2) 634-643;
Aaron Janowsky
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Clifford Mah
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Robert A. Johnson
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Christopher L. Cunningham
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Tamara J. Phillips
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John C. Crabbe
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Amy J. Eshleman
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John K. Belknap
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Abstract

Binding of 3β-(4-iodophenyl) tropane-2β-carboxylic acid methyl ester ([125I]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 proopiomelanocortin pseudogenePomc-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.

Footnotes

  • This work was supported by the Department of Veterans Affairs Research Career Scientist and Merit Review Programs (A.J., J.K.B., J.C.C., T.J.P.), U.S. Public Health Service Contract N0l-DA-7-8071, and Grants P50AA10760, DA10913, DA05228, and DA11547.

  • Abbreviations:
    DA
    dopamine
    DAT
    dopamine transporter
    RI
    recombinant inbred
    QTL
    quantitative trait locus
    RTI-55
    3β-(4-iodophenyl) tropane-2β-carboxylic acid methyl ester
    SERT
    serotonin transporter
    LOD
    logarithm of the odds
    COC
    cocaine
    MA
    methamphetamine
    MDS
    multidimensional scaling
    cM
    centiMorgan
    • Received October 30, 2000.
    • Accepted April 20, 2001.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 298 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 2
1 Aug 2001
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Research ArticleNEUROPHARMACOLOGY

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 and John K. Belknap
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 634-643;

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Research ArticleNEUROPHARMACOLOGY

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 and John K. Belknap
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 634-643;
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