Dluzen Dean E, Anderson Linda I, Pilati Charles F
Department of Anatomy, Northeastern Ohio Universities College of Medicine (NEOUCOM), Rootstown, OH, USA.
Neurotoxicol Teratol. 2002 Mar-Apr;24(2):267-73. doi: 10.1016/s0892-0362(02)00187-3.
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.
甲基苯丙胺（MA）相关死亡和黑质纹状体多巴胺能（NSDA）神经毒性在男性中更为严重。这种性别差异的确切原因尚不清楚，但有数据表明雌激素（E）可作为心血管系统和NSDA系统的保护剂，这提示性腺类固醇在调节对这种精神兴奋剂的毒性方面具有重要作用。在本报告中，我们研究了性腺类固醇激素E和睾酮（T）对完整和去势的雌性及雄性CD-1小鼠中MA诱导毒性的影响。用E处理完整雄性小鼠会对MA产生严重的急性毒性，MA处理后24小时仅有41%（7/17）的雄性存活。这种死亡率与接受相同MA给药方案的未接受激素处理的小鼠显著不同[存活率为94%（16/17）]。其他处理组均未显示出与未接受激素处理的小鼠有显著差异的死亡率。E处理的雌性小鼠（完整或去势）纹状体多巴胺（DA）浓度显著高于未接受激素处理的小鼠，而未接受激素处理的小鼠之间在统计学上无差异。为了理解E处理的完整雄性小鼠死亡率的一些原因，我们从另一组接受或未接受E处理的完整雄性小鼠中测量了体温、心率和心脏儿茶酚胺浓度。与未接受E处理的雄性相比，E处理的完整雄性小鼠心率显著降低。体温或心脏儿茶酚胺浓度未获得统计学上的显著差异。这些数据表明，MA诱导了一种严格的急性毒性，这种毒性对E处理的完整雄性小鼠具有特异性，并且与心率降低有关。此外，E可作为雌性而非雄性小鼠NSDA系统的神经保护剂。这些数据表明，在完整雄性小鼠中观察到的E引起的急性MA毒性可能是心脏功能改变所致。因此，性腺类固醇激素可作为MA中枢和外周毒理学效应的关键调节因子。
