Genetic alteration in the dopamine transporter differentially affects male and female nigrostriatal transporter systems.

Genetic alteration in the dopamine transporter differentially affects male and female nigrostriatal transporter systems.

Ji Jing; Bourque Melanie; Di Paolo Therese; Dluzen Dean E

Biochemical pharmacology

2009

2009-12

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.

Animals; Corpus Striatum/*metabolism; Dopamine Plasma Membrane Transport Proteins/*genetics; Female; Male; Messenger/biosynthesis; Mice; Mutant Strains; Protein Binding; Reserpine/pharmacology; RNA; Sex Characteristics; Substantia Nigra/*metabolism; Vesicular Monoamine Transport Proteins/antagonists & inhibitors/biosynthesis/*physiology

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