Estrogen acts as a neuroprotectant of the nigrostriatal dopaminergic system when given chronically to female mice prior to Methamphetamine (MA) insult. In this report, we tested the acute effects of Estradiol Benzoate (EB-10 microg in Oil) in ovariectomized CD-1 mice to function as a neuroprotectant when administered prior to (Experiment 1) or after (Experiment 2) MA treatment. Striatal dopamine (DA) concentrations and DOPAC/DA ratios were measured to assess the neuroprotective effects of EB. In Experiment 1, we observed that EB exerted a neuroprotective effect upon striatal dopamine concentrations when administered at 24 and 12, but not at 0.5, hours prior to MA injection and upon DOPAC/DA ratios when administered at 24, 12 and 0.5 hours prior to MA. In Experiment 2, no evidence for estrogen to protect the striatum from MA insult was obtained when EB was administered at 15, 30, 60 or 120 minutes after MA. These results show that EB can act as a modulator of MA-induced nigrostriatal dopaminergic neurotoxicity suggestive of a neuroprotectant, when administered within 0.5 hour of MA insult as assessed by measures of DOPAC/DA, but fails to prevent depletion of DA when given after MA insult. The data suggest that estrogen may exert this rapid neuroprotective effect through a non-genomic mechanism.

Our laboratories have shown the positive effect of estradiol on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- and methamphetamine (MA)-induced striatal dopamine (DA) depletion. Most studies on E neuroprotection use chronic administration of the steroid to evaluate its beneficial effect. In the present report, we investigated the neuroprotective potential of 17β-estradiol-3-benzoate (E) under acute conditions when administered 24, 12 or 0.5 h before MA. The effects of E on striatal DA and dihydroxyphenylacetic acid (DOPAC) contents, and DA transporter (DAT) protein and mRNA were measured using high-performance liquid chromatography, autoradiography and in situ hybridization, respectively. We observed neuroprotection with an acute dose of E, and also that protection presents a different time course for each dopaminergic marker. DAT mRNA responded more quickly to E than its protein (at 0.5 h vs. 24 h). Also, E treatment 12 h prior to MA resulted in ‘normal’ (equal to control) DA content, while DAT protein was still decreased as compared to control values. These different responses for each marker may represent different mechanisms of action of E (genomic versus nongenomic). Since most experimental studies use DA content as the sole indicator of nigrostriatal toxicity and examine a single time point following chronic E administration, the present results demonstrate the importance of evaluating differences in temporally dependent responses of DA, DAT protein and mRNA, to achieve a more comprehensive indication of the nigrostriatal state and the means by which E can function as a neuroprotectant in this system.

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