Research reportThe effect of testosterone upon methamphetamine neurotoxicity of the nigrostriatal dopaminergic system
Introduction
There exists a clear sex difference of the nigrostriatal dopaminergic (NSDA) system in response to neurotoxins. For example, it was shown that male mice display greater striatal dopamine (DA) depletion after MPTP-treatment [6]. Moreover, administration of high doses of methamphetamine (MA) produces more severe striatal DA depletions in male compared with female Swiss–Webster mice [42], [43], [44]. Such sex differences have a direct clinical correlate since MA related deaths are relatively lower in women [28].
In an attempt to understand the exact basis for these sex differences in response to neurotoxins, most work has focused on the female gonadal steroid hormone, estrogen (E). E clearly plays an important role in modulating NSDA function in response to neurotoxins [13], [16], [17], [37]. Within our laboratory, we found that the gonadectomized female, as well as male, C57/B1 mice-treated with E showed significantly higher striatal DA concentrations than those without E-treatment following MPTP administration [19]. Moreover, E has been shown to act as a neuroprotectant of MPTP neurotoxicity within intact male mice [25]. We also observed a modulatory effect of E upon NSDA neurotoxicity in the 6-OHDA-treated rat, with significantly greater striatal DA concentrations being obtained within the 6-OHDA infused side in E-treated ovariectomized rats [12]. In addition, E can function as a neuroprotectant of MA-induced NSDA neurotoxicity in ovariectomized (OVX) CD-1 mice, and this neuroprotective effect of E is abolished in the presence of the anti-E, tamoxifen [24].
In contrast to that of E, the influence of the male gonadal steroid hormone, testosterone (T), upon NSDA neurotoxicity has received relatively little attention. T, like E, has a clear modulatory effect upon the NSDA system. This follows from data which show that marked increases in striatal catecholamine synthesis [22], DA metabolites [4] and in vitro DA release [20] are obtained in male rats following castration. These modulatory effects of T are also seen from a variety of the indirect indices of NSDA function. For example, castrated male rats show increased locomotor activity [2], [3], [20] and T attenuates the effects of amphetamine on locomotor activity and stereotyped behavior [1], [15], [36], [38]. Such an inverse relationship between T and dopaminergic activity may have direct clinical significance since schizophrenics, who are typically characterized as having excessive dopaminergic activity, have low plasma T levels [5]. With regard to T and NSDA neurotoxicity, there are data which show that the amount of l-DOPA evoked DA output from superfused striatal tissue fragments of orchidectomized+T-treated CD-1 mice receiving MPTP was significantly decreased compared with that of orchidectomized non-T-treated and MPTP vehicle-treated mice [10]. However, no effect of T was observed upon striatal DA concentrations following MPTP-treatment in either CD-1 or C57/Bl mice [10], [11], [26].
In order to evaluate the interaction of T upon NSDA neurotoxicity, in the present experiments we tested the effects of T upon MA neurotoxicity in female mice as well as the effects of T and E upon MA neurotoxicity in male mice. Since MA represents a drug of abuse with increasing popularity, is neurotoxic in non-human primates and rodents and shows clear sex differences in this neruotoxicity, the capacity for gonadal steroid hormones to modulate MA-induced effects upon the NSDA system represents an important area of investigation. In particular, there are no data on the issue of whether the male gonadal steroid hormone, T, would alter MA-induced neurotoxicity upon the NSDA system. Accordingly, two sets of experiments were performed whose overall goal was to examine the interactions of gonadal steroid hormones and MA neurotoxicity of the NSDA system. The purpose of Experiment 1 was to examine if T would act as a modulator of MA neurotoxicity of the NSDA system in OVX female mice. In this experiment, we were interested in determining whether T may be contributing to the gender differences in MA-induced neurotoxicity of the NSDA system and in this way enhance the degree of NSDA neurotoxicity when administrated to OVX females. The purpose of Experiment 2 was to examine if either E or T would act as a modulator of MA neurotoxicity in castrated male CD-1 mice. While it was expected that T should not exert any effects, the question of whether E would act as a neuroprotectant against MA-induced NSDA neurotoxicity within the male has yet to be addressed. To accomplish these goals, both striatal DA concentrations and output were determined from gonadectomized CD-1 mice subjected to the two hormonal treatments of the experiments. These two measures (DA concentration and output) were included to provide a more comprehensive assessment and compare these two parameters of NSDA function in response to this treatment.
Section snippets
Animals
Retired breeder CD-1 female and male mice were used as subjects in the present experiments. Retired breeder mice were used since they better model the age period of onset of neurodegeneration and are more sensitive to the effect of neurotoxins [9], [27]. All animals were housed in the NEOUCOM vivarium under a 12 h light–12 h dark cycle, with lights on at 0600 h. Water and Lab chow were available ad libitum. All mice were gonadectomized. Gonadectomies were performed while the mice were under
DA concentration
A summary of the striatal DA concentrations from the different treatment conditions of Experiment 1 is presented in Fig. 1. Analysis of these data indicate an overall statistically significant difference among the three groups (F2,21=44.7, P<0.0001). Post-hoc comparisons reveal that maximal DA concentrations were obtained with the vehicle-treated mice and these levels were significantly greater than both the MA and T+MA groups (P<0.0001 for both). No statistically significant differences were
Discussion
The results of the striatal DA tissue concentrations from Experiment 1 indicate that T-treatment neither exacerbates nor protects against neurotoxicity of the NSDA system induced by MA in OVX female CD-1 mice. This follows since there were no significant differences in striatal DA concentrations between the T- and non-T-treated groups in response to MA. In Experiment 2 we examined whether E or T could modulate NSDA function in response to MA-induced neurotoxicity in castrated male CD-1 mice.
Acknowledgements
We want to thank Linda Anderson for her help conducting these experiments.
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