SEX DIFFERENCES OF NEUROTRANSPORTERS WITHIN THE NIGROSTRIATAL DOPAMINERGIC SYSTEM

by Ji, Jing

JI, JING M.S. DECEMBER 2008 BIOMEDICAL SCIENCES SEX DIFFERENCES OF NEUROTRANSPORTERS WITHIN THE NIGROSTRIATAL DOPAMINERGIC SYSTEM Director of Thesis: Dean E. Dluzen The purpose was to examine the sex differences of VMAT-2 and DAT of the NSDA system in female and male mice. Two series experiments were performed: the first consisted of an in vivo experiment using reserpine-treated CD-1 mice; the second was in vitro experiment using DAT wild type and heterozygous mice. For the in vivo experiments, after treatment with reserpine, male mice showed significantly greater DA concentrations and K+-evoked DA output from the striatum. By contrast, no statistically significant sex differences were present in the response to MA-evoked DA output in reserpine-treated mice. As for the in vitro experiments, I measured DA and DOPAC contents in the corpus striatum and olfactory tubercle, and DA output induced by K+ and MA, and we compared effects of the VMAT-2 inhibiting drug reserpine upon the striatal dopaminergic function among male and female DAT wild type (+/+) and heterozygous (+/-), intact and gonadectomized mice. Striatal DA and DOPAC concentrations of female +/- DAT mice were significantly decreased as compared with wild type (+/+) controls and male +/- DAT mice. MA-evoked DA was increased in male and female +/- mice. While MA-evoked DA was significantly increased in +/+ males versus +/+ females, the +/- females showed the highest DA responses; thereby showing a reversal in the results seen in wild-type conditions. Potassium-stimulated DA was increased in male and female +/- DAT mice and maximally stimulated DA was obtained from +/- DAT females, although these mice showed the lowest DA concentrations. Infusion of reserpine-evoked DA output was significantly greater from intact +/+ and +/- female compared to male mice. The DA output profile differed markedly between +/+ and +/- females, but no such qualitative differences were present in males. Significantly increased reserpine-evoked DA responses were also obtained in +/+ and +/- gonadectomized female mice treated or not with estrogen as compared with respective responses from males. I can conclude that: 1) a deficiency in the DAT interacts with the sex of subject, 2) +/- DAT females show more extreme changes in dopaminergic responses, 3) females possess a more active VMAT-2/DA storage capacity, 4) the two transporter systems, DAT and VMAT-2, may be linked with each other and be affected differentially by the sex, 5) estrogen might contribute to this interaction between the DAT and VMAT-2, 6) the importance for understanding the sex differences present in the NSDA system in both healthy and diseased conditions.