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.
Dluzen
Dean E
DE
Department of Anatomy, Northeastern Ohio Universities College of Medicine (NEOUCOM), Rootstown, Ohio 44272-0095, USA. ded@neoucom.edu
McDermott
Janet L
JL
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D012727:Sex Characteristics; D013378:Substantia Nigra / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
D008694:Methamphetamine; D004298:Dopamine