Methamphetamine-gonadal steroid hormonal interactions: effects upon acute toxicity and striatal dopamine...

Methamphetamine (MA)-related deaths and nigrostriatal dopaminergic (NSDA) neurotoxicity are greater in males. The exact basis for this gender difference is not known, but data, which show that estrogen (E) can function as a protectant of both the cardiovascular and NSDA systems, suggest an important role for gonadal steroids in modulating toxicity to this psychostimulant. In the present report, we examined the effects of treatment with the gonadal steroid hormones E and testosterone (T) upon MA-induced toxicity within intact and castrated female and male CD-1 mice. Treatment of intact males with E produced a severe acute toxicity to MA, with only 41% (7/17) males surviving at 24-h post-MA. This incidence of mortality was significantly different from that of nonhormonally treated mice receiving an identical regimen of MA [94% survival (16/17)]. None of the other treatment groups showed mortality rates, which differed significantly from the nonhormonally treated mice. Striatal dopamine (DA) concentrations of E-treated female mice (intact or castrated) were significantly greater than that of the nonhormonally treated mice, which failed to differ statistically among each other. In an attempt to understand some of the bases for the mortality rates in E-treated intact males, body temperatures, heart rates and heart catecholamine concentrations were measured from an additional group of intact male mice treated or not treated with E. Heart rates of E-treated intact males were significantly decreased compared with non-E-treated males. No statistically significant differences were obtained for body temperatures or heart catecholamine concentrations. These data demonstrate that MA induces an exacting, acute toxicity, which is specific for E-treated intact male mice and is associated with a reduction in heart rate. In addition, E can function as a neuroprotectant of NSDA system within female, but not male, mice. These data suggest that acute MA toxicity observed with E in intact male mice may result from a change in cardiac function. Accordingly, gonadal steroid hormones can function as critical modulators of both central and peripheral toxicological effects of MA.