Biomedical subjects

Janet L McDermott

Publications and source records attributed to Janet L McDermott.

4 recordsLinked to original sources

PubMed2006

Estrogen, testosterone, and methamphetamine toxicity.

The gonadal steroid hormone, estrogen, can diminish the degree of striatal dopamine depletion resulting from methamphetamine. In this article, we describe the conditions of this estrogen neuroprotection as well as the potential for estrogen and testosterone to enhance methamphetamine-induced neurodegeneration of the nigrostriatal dopaminergic system. When administered prior to a neurotoxic regimen of methamphetamine, estrogen significantly decreases the amount of striatal dopamine depletion in intact or gonadectomized female, but not male, mice. This capacity for estrogen to function as a neuroprotectant can occur quite rapidly, at 30 min prior to methamphetamine administration, and with relatively low doses of estrogen (1 microg estradiol benzoate). Estrogen remains an effective neuroprotectant in neonatally gonadectomized female mice treated with testosterone, but not in female mice that were gonadectomized prior to puberty. Nor does estrogen demonstrate any beneficial effects when administered after methamphetamine. Recent data have indicated some conditions where gonadal steroids can increase the extent of striatal neurodegeneration in response to methamphetamine. Specifically, when some existing perturbation is present in the nigrostriatal dopaminergic system, treatment with estrogen enhances the extent of striatal dopamine depletion to methamphetamine. Similarly, increased striatal dopamine depletion to methamphetamine is observed in gonadectomized male mice treated with testosterone.

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PubMed2004

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.

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PubMed2002

Striatal dopamine output is compromised within +/- BDNF mice.

We reported previously that mice lacking one brain-derived neurotrophic factor (BDNF) allele demonstrate elevated striatal dopamine (DA) concentrations but impaired behavioral responses involving the nigrostriatal dopaminergic (NSDA) system. To test the hypothesis that these elevated striatal DA concentrations are associated with perturbed NSDA functioning, we compared striatal DA output between heterozygous mutant (+/-) and wild-type littermate control (+/+) BDNF mice under conditions of an intact NSDA system, as well as following methamphetamine (MA)-induced neurotoxicity. Basal DA output from superfused CS tissue fragments did not differ between +/+ and +/- BDNF mice. Potassium (K+) stimulated DA outputs from intact striatal fragments of +/+ mice were significantly greater than that of +/- BDNF mice. Following MA treatment, K+ stimulated DA output of +/+ mice was statistically equivalent to +/- BDNF mice. Striatal DA concentrations of +/- BDNF mice were elevated, albeit not significantly, in both intact and MA-treated mice relative to +/+ mice. Following MA treatment, striatal DA concentrations were significantly decreased for both genotypes; however, the degree of DA depletion was significantly greater in +/+ mice. Analyzed collectively, these data show the differential effects exerted by a BDNF mutation upon striatal DA concentrations and output. Notably, lower striatal DA concentrations of +/+ vs. +/- BDNF mice can be contrasted with the significantly greater K+ stimulated DA output from the former. This difference was abolished following MA treatment. These results suggest that processes involved with the dynamics of DA release within the NSDA system may be compromised in +/- BDNF mutant mice.

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PubMed2002

Estrogen, anti-estrogen, and gender: differences in methamphetamine neurotoxicity.

In Part 1 of this report, we review data on the effects of estrogen (E), the anti-E tamoxifen (TMX), and testosterone (T) on methamphetamine (METH)-induced neurotoxicity in female and male CD-1 mice. Treatment of gonadectomized females with a physiological regimen of E significantly diminished the amount of striatal dopamine (DA) depletion to METH compared with non-E-treated mice. If these E-treated mice received coadministered TMX, the neuroprotective effects of E were abolished. However, TMX administration to either intact female or male mice appeared to exhibit a neuroprotective effect. Whereas E administration one week before METH treatment serves as a neuroprotectant, reversing the treatment order (METH-->one week-->E) failed to indicate any neurorestorative effects for E. This striatal DA-preserving effect of E was gender specific, because males receiving an identical treatment of E followed by METH failed to show any evidence of neuroprotection, nor did the predominantly male gonadal steroid hormone T afford any neuroprotection in gonadectomized male or female mice. In the second part of the report, we direct our attention toward examining some of the means by which E can exert this neuroprotective effect. The findings that gonadectomized female, but not intact male, mice treated with E show a significant reduction in body temperature can contribute to the gender-specific METH neuroprotection. E also diminishes the initial amounts of DA evoked by METH, as observed when E is co-infused with METH into superfused striatal tissue fragments of gonadectomized female and male mice. By contrast, T tends to increase METH-evoked DA responses. Finally, differences in mRNA levels were obtained between male and female mice treated with METH. Intact female mice tend to show greater levels of striatal glial fibrillary acidic protein and decreased levels of plasminogen activator inhibitor-1 compared with males. Each of these factors, combined with our previous findings that E can inhibit DA transporter function, represent significant events contributing to E/gender-dependent effects on METH neurotoxicity.

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