Genetic alteration in the dopamine transporter differentially affects male and female nigrostriatal transporter systems.
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.
Ji
Jing
J
Department of Anatomy, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA.
Bourque
Mélanie
M
Di Paolo
Thérèse
T
Dluzen
Dean E
DE
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D012110:Reserpine / Q000494:pharmacology; D012727:Sex Characteristics; D013378:Substantia Nigra / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*
D050483:Dopamine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D012110:Reserpine