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 μg 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.