Effect of estrogen upon methamphetamine-induced neurotoxicity within the impaired nigrostriatal dopaminergic system

In the present study, we investigated whether estrogen remains effective as a neuroprotectant within an impaired nigrostriatal dopaminergic (NSDA) system of gonadectomized female and male mice. In Experiment 1, mice were treated with four different regimens of methamphetamine (MA) to establish a protocol for an impaired NSDA system to be used in subsequent experiments. Based upon the results of Experiment 1, in Experiment 2 gonadectomized female mice received a treatment with either control (saline), low- or high-dose of MA to produce an initial NSDA impairment. At one week post-MA, mice received either estradiol benzoate (10 microg) or vehicle followed 24 h later with low-MA or saline. Estrogen altered the toxic effects of the second invasion of MA as indicated by a significant decrease in striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations. In addition, DA and DOPAC depletion was greater in high- vs. low-dose MA. In gonadectomized male mice (Experiment 3), striatal DA and DOPAC concentrations showed greater decreases following high-, vs. low-doses of MA; however, estrogen did not alter these responses. These results demonstrate that the capacity for estrogen to protect or worsen MA-induced neurotoxicity of dopaminergic neurons is limited to female mice and depends on the condition of the NSDA system.