Genetic alteration in the dopamine transporter differentially affects male and female nigrostriatal transporter systems |
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Authors: | Jing Ji,Mé lanie Bourque,Thé rè se Di Paolo,Dean E. Dluzen |
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Affiliation: | a Department of Anatomy, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA b Department of Environmental and Occupational Health, University of Pittsburgh, PA 15219-3130, USA c Molecular Endocrinology and Genomic Research Center, Laval University Medical Center, CHUL, Quebec City, G1V 4G2 Canada d Faculty of Pharmacy, Laval University, Quebec City, G1K 7P4, Canada |
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Abstract: | Female mice with a heterozygous mutation of their dopamine transporter (+/− DAT) showed relatively robust reductions in striatal DAT specific binding (38-50%), while +/− DAT males showed modest reductions (24-32%). Significant decreases in substantia nigra DAT specific binding (42%) and mRNA (24%) were obtained in +/− DAT females, but not +/− DAT males (19% and 5%, respectively). The effects of this DAT perturbation upon vesicular monoamine transporter-2 (VMAT-2) function revealed significantly greater reserpine-evoked DA output from +/+ and +/− DAT female as compared to male mice and the DA output profile differed markedly between +/+ and +/− DAT females, but not males. No changes in VMAT-2 protein or mRNA levels were present among these conditions. On the basis of these data, we propose: (1) a genetic mutation of the DAT does not exert equivalent effects upon the DAT in female and male mice, with females being more affected; (2) an alteration in the DAT may also affect VMAT-2 function; (3) this interaction between DAT and VMAT-2 function is more prevalent in female mice; and (4) the +/− DAT mutation affects VMAT-2 function through an indirect mechanism, that does not involve an alteration in VMAT-2 protein or mRNA. Such DAT/VMAT-2 interactions can be of significance to the gender differences observed in drug addiction and Parkinson's disease. |
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Keywords: | ANOVA, analysis of variance DA, dopamine DAT, dopamine transporter EDTA, ethylenediaminetetraacetic acid KRP, kreb's ringer phosphate MPP+, 1-methyl-4-phenylpyridinium 6-OHDA, 6-hydroxydopamine VMAT-2, vesicular monoamine transporter-2 WT, wild type |
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