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Abstract: A neurotoxic regimen of methamphetamine (MA—40 mg/kg ip) administered at 0 (control—MA vehicle), 0.5 and 72 h prior to determinations of striatal dopamine (DA) and DOPAC (3,4-dihydroxyphenylacetic acid)/DA ratios were compared among juvenile and adult female and male mice. Adult females and males showed similar depletions in striatal DA at 0.5 h post-MA, but males showed greater DA depletions and DOPAC/DA ratios at 72 h post-MA. Juvenile mice showed neither sex differences, nor any MA neurotoxicity upon striatal DA or DOPAC/DA ratios. Following MA, body temperatures increased in all mice, but increases in adult males were greater than adult females; juveniles showed no sex differences and body temperature increases were similar to that of adult males. MA-evoked DA output was greater in adult compared to juvenile males and a biologically effective regimen of testosterone to juvenile males neither increased MA-evoked DA output nor decreased MA-induced striatal DA like that observed in adult males. These results demonstrate: (1) Unlike adults, juvenile mice show neither a sex difference for MA-induced neurotoxicity or body temperature increases, nor MA neurotoxicity, (2) Initial effects of MA (0.5 h) in adult females and males are similar, but at 72 h post-MA females show no further striatal DA depletion, (3) Increased striatal DA depletion within adult versus juvenile males may be related to initially higher MA-evoked DA responses, and (4) Testosterone fails to convert juvenile males into adults with regard to MA effects. [Copyright &y& Elsevier]

Men and women differ with regard to their use of, and responses to, methamphetamine (MA). Analogous sex differences with regard to MA are observed in animal models. In this report, data from a series of experiments that focus upon dopamine transporter (DAT) and vesicular monoamine transporter2 (VMAT2) function are reviewed by way of providing some understanding for these sex differences to MA. The amount of dopamine (DA) recovered after infusion of DA into superfused striatal tissue was greater in females and an accentuated amount of extracellular DA was obtained from females after infusion of the DAT-blocking drug, nomifensine. These data suggest a higher level of DAT activity in females. To evaluate the implications of this sex difference in DAT function as related to MA, the amount of DA evoked by an infusion of MA into superfused striatal tissue was tested and found to be significantly greater in males. In contrast, potassium chloride–stimulated DA release was greater in females. The results of these DA-evoked experiments imply that the greater DAT activity of females, by itself, cannot explain the sex differences observed with MA, and our attention was then directed to the VMAT2. Administration of the VMAT2 blocker, reserpine, in vivo resulted in a significantly greater amount of striatal DA depletion within female mice and infusion of reserpine in vitro into striatal tissue produced significantly greater levels of extracellular DA in females. The data of these reserpine experiments suggest that females possess a more active/efficient VMAT2 function. Collectively, the data provide evidence for sex differences in both DAT and VMAT2 functioning, and we propose that the interaction of these two transporter systems contributes to the differences in response to MA between males and females. [ABSTRACT FROM AUTHOR]

Abstract: In this report a series of six in vitro experiments in which reserpine-evoked dopamine output and two in vivo experiments in which the effects of reserpine injections upon dopamine content from striatal tissue of female and male mice were performed as a means to assess possible sex differences in vesicular monoamine transporter 2 (VMAT2) function. Significantly greater amounts of dopamine were obtained from striatal tissue of female mice in response to either a brief (experiment 1) or continuous (experiment 2) infusion of reserpine. Similarly, reserpine-evoked dopamine output from striatal tissue of gonadectomized females was significantly greater that that of gonadectomized males (experiment 3). When reserpine-evoked dopamine responses were compared directly between intact versus gonadectomized females (experiment 4) or males (experiment 5) no statistically significant differences were obtained. Finally, comparisons of gonadectomized females treated or not with estrogen revealed no statistically significant differences in reserpine-evoked dopamine output (experiment 6). Injections of reserpine produced significantly greater depletions of striatal dopamine content within intact female versus male mice (experiment 7). Dopamine contents of gonadectomized females treated or not with estrogen did not differ following treatment with reserpine, but were significantly greater than that of gonadectomized males (experiment 8). Taken together, these results show that female striatal tissue is more responsive to reserpine-evoked dopamine output, and this sex difference appears to be estrogen independent. Similarly, the dopamine depleting effects of reserpine are greater in intact female mice, however, gonadectomy reverses this effect in an estrogen independent manner. The data suggest that female mice may have a greater amount/activity of VMAT2 function as revealed by the increased responsiveness to the VMAT2 blocking drug, reserpine. Such differences in VMAT2 function may be related to the gender differences observed in conditions like Parkinson''s disease and drug addiction. [Copyright &y& Elsevier]

Abstract: In this report the potassium- (30 mM) and amphetamine- (10 μM) stimulated responses of dopamine (DA) and 3,4-dihydroxy phenylacetic acid (DOPAC) from superfused striatal tissue of female and male mice as sampled at 2, 6, 18 and 24 months of age were compared. When assessed relative to responses obtained from 2-month-old female mice, potassium-stimulated DA output of female mice was significantly decreased at 18 months of age and significantly increased at 24 months of age. In male mice, the only statistically significant change was an increase in potassium-stimulated DA in the 24 versus 2-month-oldmice. In response to amphetamine-stimulation, DA responses from striatal tissue of 18-month-old females were significantly decreased and that of 24-month-old mice significantly increased relative to that of the 2-month-old females. In the case of male mice, amphetamine-stimulated DA responses of 6- and 18-month-old mice were significantly decreased compared with responses observed in the 2-month-old males.In addition, amphetamine-stimulated DA responses of the 24-month-old females were significantly greater than the 24-month-old males. In general, the response profiles for DOPAC to potassium and amphetamine stimulation were similar to that of DA for male, but not female, mice. These results demonstrate that sex differences in striatal dopaminergic function are differentially affected by age. Overall, striatal DA responsiveness of female mice shows more extreme age-related changes, particularly between the 2- and 6-month versus the 18- and 24-month-old mice and a discord between DA and DOPAC responses. Such extreme changes may be related to the presence (at 2 and 6 months) versus absence (at 18 and 24 months) of estrous cycles/gonadal steroid hormonal functions in female mice. [Copyright &y& Elsevier]

The gonadal steroid hormone, estrogen, has the capacity to function as a neuroprotectant against methamphetamine (MA)-induced neurotoxicity of the nigrostriatal dopaminergic system within female, but not male, mice. In an attempt to understand some of the bases for this effect of estrogen, the incipient effects of MA upon evoked dopamine output from superfused striatal tissue fragments of gonadectomized female and gonadectomized as well as intact male mice were evaluated under conditions where estrogen (or testosterone) was present in the medium. The amount of dopamine evoked by MA was significantly reduced when estrogen was co-infused with MA. This attenuation was obtained with striatal tissue fragments of gonadectomized female and gonadectomized and intact male mice. In contrast to estrogen, co-infusion of testosterone failed to produce an overall statistically significant change in MA-evoked dopamine output within superfused striatal tissue fragments of gonadectomized female and male mice. In this way, the gonadal steroid hormones, estrogen and testosterone, exert differential modulatory effects upon MA-evoked dopamine output from superfused striatal tissue fragments. However, similar effects to these gonadal steroid hormones were observed between gonadectomized female and gonadectomized or intact male mice. These data reveal an absence of a sexual dimorphism in striatal responsiveness with regard to estrogen’s ability to alter MA-evoked DA output. Accordingly, the sexually dimorphic capacity for estrogen to function as a neuroprotectant may involve a composite of actions upon the nigrostriatal dopaminergic system involving events/sites other than the initial stimulation of dopamine output. [Copyright &y& Elsevier]