Developmental and Genetic Influences upon Gender Differences in Methamphetamine‐Induced Nigrostriatal Dopaminergic Neurotoxicity

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Abstract
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.