Sex Differences in Methamphetamine-Evoked Striatal Dopamine Output Are Abolished following Gonadectomy: Comparisons with Potassium-Evoked Output and Responses in Prepubertal Mice

Abstract

Sex differences are reported for methamphetamine (MA)-induced neurotoxicity of the nigrostriatal dopaminergic system. In an attempt to understand some of the bases for these differences, we investigated MA-evoked dopamine (DA) responses from superfused striatal tissue fragments of intact and male and female CD-1 mice. These responses were compared with that of gonadectomized mice, potassium-evoked DA responses in intact mice and responses in prepubertal mice. In experiment 1, DA responses were tested using infusion of MA at doses of 1, 10, 100 and 1,000 µM. In intact mice, mean peak MA-evoked DA responses were consistently increased and significantly greater in male vs. female mice at the 1,000 µM dose. No such significant differences were observed between gonadectomized male vs. female mice (experiment 2). In contrast to MA, potassium-stimulated DA responses were increased in intact female mice, with statistically significant differences at doses of 30 and 60 mM (experiment 3). No statistically significant differences between intact prepubertal male and female mice were obtained in response to a 1,000 µM dose of MA (experiment 4) or to a 60 mM dose of potassium (experiment 5). These results indicate that intact male mice show greater sensitivity to MA-evoked DA output. This sex difference is abolished following gonadectomy, is not observed with potassium, nor is it present in prepubertal mice. The increased sensitivity to MA shown by intact males may be related to the greater degree of striatal dopaminergic neurotoxicity observed in male mice in response to this psychostimulant and appears to be attributable to differences in gonadal steroid hormones between male and female mice.