Developmental and genetic influences upon gender differences in methamphetamine-induced nigrostriatal dopaminergic neurotoxicity.

The gonadal steroid hormone estrogen (E) may play an important role in sex differences in methamphetamine (MA)-induced neurotoxicity of the nigrostriatal dopaminergic (NSDA) system because E can serve as a neuroprotectant in female, but not male, mice. Gonadal steroid hormones also exert important organizational/developmental effects upon the brain at critical developmental periods. In Part 1 we assessed whether organizational (neonatal) or developmental (prepubertal) effects of gonadal steroids would alter gender/E-dependent neuroprotection of MA-induced NSDA neurotoxicity. Attempts to feminize male mice by gonadectomy at either the neonatal or prepubertal period failed to enable E to function as a neuroprotectant within the adult male mouse. Attempts to masculinize the female by testosterone administration at the neonatal period did not abolish the capacity for E to function as a neuroprotectant. However, prepubertal gonadectomy of female mice did disrupt E's capacity to serve as a neuroprotectant. These results suggest that genetic sex may prove the primary determinant for the sex differences observed in response to MA-induced NSDA neurotoxicity. In Part 2 we examined whether gender differences in response to MA-induced NSDA neurotoxicity would interact with a specific genetic alteration in a neurotrophic factor, brain-derived neurotrophic factor (BDNF). Female and male mice that were either deficient (+/- BDNF) or overexpressing (DBH:BDNF+) BDNF were treated with MA. Sex differences in MA-induced NSDA neurotoxicity remained present in +/- BDNF mice and were less severe as compared with their wild-type controls. A similar result was obtained in mice that overexpress BDNF, with female and mutant mice showing less NSDA neurotoxicity. In both BDNF-deficient mice and mice that overexpress BDNF, the relative degree of MA-induced NSDA neurotoxicity was lower in males. Taken together, these results suggest that a selective alteration in BDNF expression offers some neuroprotective potential against MA-induced NSDA neurotoxicity, and the relative degree of this neuroprotection may interact with the gender of the subject.