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      Ovarian Hormones Do Not Attenuate Methamphetamine-Induced Dopaminergic Neurotoxicity in Mice Gonadectomized at 4 Weeks Postpartum

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          The present study was undertaken to assess the ability of ovarian hormones to alter methamphetamine (MA)-induced dopaminergic toxicity in male and female mice gonadectomized at 4 and 6 weeks of age. None of the following three treatments, estradiol benzoate (EB, 3 × 0.47 µg), progesterone (Prog, 3 × 0.47 µg), or EB (2 × 0.47 µg) followed by Prog (0.47 µg), affected the dopamine (DA)-depleting effects of MA in male and female mice gonadectomized when they were 4 weeks old. However, in contrast to the findings that male mice are more sensitive to MA-induced DA depletion than female mice, no sexual differences in the sensitivity to MA treatment were observed in mice gonadectomized at this age. Moreover, three daily doses of EB (0.47 µg) and EB (0.47 µg) combined with 4-hydroxytamoxifen (4OHT, 6 µg) effectively attenuated striatal DA depletion produced by MA in female mice ovariectomized at 6 weeks of age. Three daily doses of Prog (0.47 µg) and EB (0.47 µg) combined with 4OHT (6 µg) significantly attenuated MA-induced striatal DA depletion in male mice gonadectomized at 6 weeks of age. Taken together, the modulating effects of ovarian hormones on MA-induced DA depletion in mouse striatum could be sex- and age-dependent. 4OHT did not block the protecting effects of EB on MA-induced DA depletion in female and male mice, suggesting that the estrogen receptor may not be involved in the protective effects of EB on attenuating MA-induced DA toxicity.

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          Most cited references 8

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          Estrogen rapidly potentiates amphetamine-induced striatal dopamine release and rotational behavior during microdialysis.

           Jill Becker (1990)
          Ovariectomy (OVX) of female rats results in a decreased behavioral response to stimulation of the mesostriatal dopamine (DA) system and decreased striatal DA release in vitro. Estrogen replacement restores both behavioral and neurochemical responsiveness. In this report, microdialysis in freely moving rats is used to simultaneously study the behavioral and neurochemical effects of systemic estradiol. OVX rats received a unilateral 6-hydroxy-dopamine lesion of the substantia nigra and then underwent microdialysis of the intact striatum. Thirty min after a single injection of 5 micrograms estradiol benzoate, amphetamine-induced rotational behavior and striatal DA release are both potentiated, relative to the response of oil-treated control animals.
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            Estradiol enhances behavioral sensitization to cocaine and amphetamine-stimulated striatal [3H]dopamine release.

            Locomotor activity and stereotypy induced by cocaine is increased or 'sensitized' after repeated cocaine administration. This behavioral sensitization may be mediated by a persistent increase in dopamine (DA) transmission in mesolimbic and nigrostriatal pathways. Since the female estrous cycle and ovarian steroid hormones appear to affect both cocaine sensitization and DA transmission, studies were undertaken to determine the effects of ovarian steroids on sensitization of the behavioral responses to repeated cocaine injections and any concomitant effects on striatal DA release. Young female adult rats were ovariectomized and 2 weeks later were implanted with chronic release forms of estradiol (E), progesterone (P), both (EP) or vehicle (V). Locomotor and stereotypic behavior were rated after an initial injection of either saline or cocaine (10 mg/kg, i.p.) and after the 8th daily injection of saline or cocaine. A significant increase in both locomotor and stereotypic behaviors was seen after the first cocaine injection relative to saline-injected animals and this response was not affected by steroid treatment. Repeated injections of cocaine caused sensitization of the initial behavioral response to cocaine (i.e. an increase in stereotypic and locomotor behavior) and the degree of cocaine sensitization was greatest in group E. Steroid treatment did not affect behavior in saline-treated rats. When striatal [3H]DA release was measured in vitro 1 or 7 days after the last injection, amphetamine-stimulated release was greater in vehicle-treated rats 7 days after cocaine injections but not 1 day after injections. In contrast, release was enhanced in group E both 1 and 7 days after cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)
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              Stereospecific prevention by 17beta-estradiol of MPTP-induced dopamine depletion in mice.

              Neuroprotective activity of estrogens is reported in Alzheimer disease and recently has also been suggested for Parkinson disease, a disease affecting more men than women. To characterize this estrogenic activity, we studied the effects of 17beta- and 17alpha-estradiol treatment (1 microg twice daily 5 days before, during the day of four MPTP (15 mg/kg) injections, and for the following 5 days) on dopamine striatal toxicity induced by the neurotoxin MPTP in retired breeder male C57BL/6 mice. Striatal dopamine concentrations and its metabolites dihydroxyphenylacetic acid and homovanillic acid measured by HPLC in MPTP mice that received 17beta-estradiol were comparable to control animals, whereas MPTP mice treated with saline or 17alpha-estradiol showed important decreases of dopamine and its metabolites. Striatal serotonin and its metabolite 5-hydroxyindoleacetic acid concentrations remained unchanged after MPTP and treatments with steroids. Striatal [(3)H]GBR 12935 binding autoradiography to the dopamine transporter was as extensively decreased and correlated with dopamine depletion in MPTP mice, whereas this transporter mRNA decrease in the substantia nigra pars compacta was less pronounced. Treatment with steroids did not significantly change [(3)H]GBR 12935 binding, whereas dopamine transporter mRNA levels were not significantly different from controls. Under the present paradigm in retired breeder male mice, our results show dopaminergic and stereospecificity of estradiol to augment dopamine levels in MPTP-lesioned mice without protecting against the extensive loss of dopamine terminals and moderate cell body loss. Copyright 2000 Wiley-Liss, Inc.

                Author and article information

                S. Karger AG
                May 2002
                29 April 2002
                : 75
                : 5
                : 282-287
                aInstitute of Behavioral Medicine, and bDepartment of Anatomy, National Cheng Kung University College of Medicine, Tainan, cPsychological Research Center, ROC Air Force Academy, Kangshan, and dDepartment of Psychology, National Taiwan University, Taipei, Taiwan
                57337 Neuroendocrinology 2002;75:282–287
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 4, References: 24, Pages: 6
                Central Effects of Gonadal Hormones


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