Sex differences in methamphetamine-evoked striatal dopamine of mice are reversed by nomifensine

Male mice show more severe striatal dopamine depletions to the psychostimulant, methamphetamine (MA). To gain some understanding for this sex difference, we examined MA-evoked dopamine (DA) responses from superfused striatal tissue fragments of male and female mice under conditions of a dopamine transporter which was either unaltered (Experiment 1) or inhibited, with use of the drug, nomifensine (Experiment 2). In Experiment 1, MA-evoked DA was significantly greater in male versus female mice. In Experiment 2, diminished, albeit statistically significant, DA responses to MA infusion in the presence of nomifensine were obtained from striatal tissue of female, but not male, mice. In Experiment 3, potassium-evoked DA responses and sex differences were abolished in the presence of nomifensine. These data demonstrate a clear sex difference in DA responses to MA. Interestingly, under conditions where dopamine transporter function is inhibited, MA retains its ability to evoke DA. However, this capacity was only observed within striatal tissue fragments of female mice and not under conditions of potassium-evoked DA. These results indicate an additional component for the bases of sex differences in nigrostriatal dopaminergic function in health and in disease. In particular, the present findings have important implications in suggesting an alternative, non-traditional, mechanism for MA effects and indicate that such a function is limited to females.