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.