Dopamine Transporter As A Marker Of Neuroprotection In Methamphetamine-lesioned Mice Treated Acutely With Estradiol
17-beta-estradiol; brain; depletion; dopamine transporter; Endocrinology & Metabolism; estrogen; gender-differences; gonadal steroids; induced neurotoxicity; methamphetamine; neuroprotection; Neurosciences & Neurology; parkinsons-disease; progesterone; rat; striatal dopamine; striatum; substantia nigra; system
D'Astous M; Gajjar T M; Dluzen D E; Di Paolo T
Neuroendocrinology
2004
1905-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1159/000079664" target="_blank" rel="noreferrer noopener">10.1159/000079664</a>
Dose-response effects of estrogen and tamoxifen upon methamphetamine-induced behavioral responses and neurotoxicity of the nigrostriatal dopaminergic system in female mice.
3; 4-Dihydroxyphenylacetic Acid/metabolism; Animal/*drug effects; Animals; Behavior; Brain Chemistry/drug effects; Dopamine/*metabolism; Dose-Response Relationship; Drug; Drug Interactions; Estrogen Antagonists/pharmacology; Estrogens/*pharmacology; Female; Methamphetamine/*toxicity; Mice; Movement/drug effects; Neostriatum/*drug effects/physiology; Neurotoxins/*toxicity; Organ Size/drug effects; Ovariectomy/methods; Stereotyped Behavior/drug effects; Substantia Nigra/drug effects/physiology; Tamoxifen/*pharmacology; Uterus
In the present experiment we evaluated the dose-response effects of estrogen (estradiol benzoate; EB) and tamoxifen (TMX) in modulating the acute behavioral and chronic effects of methamphetamine (MA) upon the nigrostriatal dopaminergic (NSDA) system in ovariectomized (OVX) mice. EB over a range of doses from 1-40 microg resulted in a neuroprotective effect upon the NSDA system as defined by both a preservation of striatal dopamine (DA) concentrations and a decrease in DOPAC/DA ratios. Interestingly, the neuroprotective effect of the 1-microg EB dose occurred in the absence of any statistically significant effect upon the bioassay parameter of uterine weight. With the exception of an increase in stereotypy time as a response to the 40-microg dose, EB at any of the doses tested failed to alter any acute behavioral responses evoked by MA. In response to TMX, a statistically significant NSDA neuroprotectant response was obtained for DOPAC/DA ratios, but not DA concentrations, to doses ranging from 12.5 to 500 microg. No statistically significant effects upon uterine weights were obtained for any of the doses of TMX tested. Behaviorally, TMX at 500 microg had the effect of increasing the amount of time spent in the center of the cage. Taken together these results demonstrate: (1) EB and TMX at relatively low doses can exert a neuroprotective effect against MA; (2) these neuroprotective effects of EB and TMX can occur in the absence of an effect upon the bioassay parameter–uterine weights; (3) the parameter of DOPAC/DA ratio may indicate a more sensitive index of NSDA neuroprotection, and (4) modulatory effects of EB and TMX upon acute behavioral responses of the NSDA system to MA can be distinguished from their neuroprotective actions.
Mickley Katherine R; Dluzen Dean E
Neuroendocrinology
2004
2004
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1159/000079710" target="_blank" rel="noreferrer noopener">10.1159/000079710</a>
Effects of estrogen and related agents upon methamphetamine-induced neurotoxicity within an impaired nigrostriatal dopaminergic system of ovariectomized mice.
3; 4-Dihydroxyphenylacetic Acid/metabolism; Androgens/administration & dosage; Animals; Dopamine Agents/*administration & dosage/toxicity; Dopamine/metabolism; Dose-Response Relationship; Drug; Drug Administration Schedule; Estradiol/administration & dosage/*analogs & derivatives/physiology; Estrogen Antagonists/administration & dosage; Female; Methamphetamine/*administration & dosage/toxicity; Mice; Neostriatum/*drug effects/metabolism; Nerve Degeneration/chemically induced/prevention & control; Neuroprotective Agents/administration & dosage; Neurotoxins/*administration & dosage; Ovariectomy; Parkinson Disease/physiopathology; Substantia Nigra/*drug effects/metabolism; Tamoxifen/administration & dosage
Estrogen increases methamphetamine (MA)-induced neurotoxicity within the impaired nigrostriatal dopaminergic (NSDA) system of ovariectomized female mice, as defined by enhanced striatal dopamine (DA) depletion. In this study we compared the effects of a lower dose of estradiol benzoate (EB, 1 microg) with related agents–tamoxifen (TMX, 12.5 microg), testosterone (5 microg) and dehydroepiandrosterone (DHEA, 3 mg) in this paradigm. In experiment 1, ovariectomized mice received an initial treatment with MA. At 1 week after MA, mice were treated with EB, TMX, testosterone, DHEA or oil vehicle and 24 h later a second MA treatment. Striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations in the MA-treated groups were decreased compared to the non-MA-treated control. Neither EB nor any of the other agents tested showed enhanced neurodegenerative or neuroprotective effects against a second MA invasion. To verify that estrogen was capable of showing a neuroprotective effect under a condition of two administrations of MA, in experiment 2, EB was administered either once or twice prior to each of the two MA treatments. EB treatment prior to the first MA invasion or first and second MA protected the NSDA system against DA and DOPAC depletion. These results imply that a lower dose of EB, TMX, testosterone and DHEA cannot exert neurodegenerative or neuroprotective effects in the impaired NSDA model. However, EB administered prior to the introduction of neurotoxicity can protect the NSDA system. This study may provide an understanding of the variations in results on the effects of estrogen upon the NSDA neurodegenerative disorder, Parkinson's disease.
Liu Bin; Dluzen Dean E
Neuroendocrinology
2006
2006
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1159/000095338" target="_blank" rel="noreferrer noopener">10.1159/000095338</a>
Gender differences in methamphetamine-induced mRNA associated with neurodegeneration in the mouse nigrostriatal dopaminergic system.
Animals; Dopamine/metabolism; Female; Inbred Strains; Male; Messenger/drug effects; Methamphetamine/*toxicity; Mice; Neostriatum/*drug effects/metabolism; Neurodegenerative Diseases/*chemically induced/genetics; Neurotoxins/*toxicity; RNA; Sex Factors; Substantia Nigra/*drug effects/metabolism
In this report female and male CD-1 mice were treated with a neurotoxic regimen of methamphetamine (MA) to compare gender differences in striatal dopamine depletion and concordant changes in mRNA markers of the transforming growth factor-beta injury response associated with neurodegeneration. Striatal dopamine concentrations of MA-treated female mice were less depleted and significantly greater than that of identically treated males. Associated with this gender difference in striatal dopamine depletion were significantly decreased mRNA levels of plasminogen activator inhibitor-1 and a trend for increased (p = 0.06) mRNA levels of glial fibrillary acidic protein within females. No statistically significant differences between MA-treated female and male mice were obtained in mRNA levels for transforming growth factor-beta, transforming growth factor-beta type 2 receptor, activin-like kinase-5 or fibronectin. These data demonstrate the presence of changes in two specific molecular markers of the transforming growth factor-beta injury response which are in accordance with gender differences in
Dluzen Dean E; Tweed Christopher; Anderson Linda I; Laping Nicholas J
Neuroendocrinology
2003
2003-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1159/000070278" target="_blank" rel="noreferrer noopener">10.1159/000070278</a>
Interactive effects of tamoxifen and estrogen upon the nigrostriatal dopaminergic system
breast-cancer; rat; receptors; Neurosciences & Neurology; Endocrinology & Metabolism; catecholamines; breast-cancer; striatum; uptake sites; amphetamine; Progesterone; female cd-1 mice; release; antiestrogens; brain metastases; chronic estradiol; ovarian steroids; sexual-behavior
Adult female rats were ovariectomized and received a 21-day release pellet containing either (17)beta-estradiol (0.1 mg), tamoxifen (5.0 mg), a combination of estradiol and tamoxifen or no further treatment. At 14 days following ovariectomy +/- hormone treatments rats were sacrificed, the corpus striatum removed and prepared for assessment of dopamine release using in vitro superfusion. Maximal potassium-stimulated dopamine release rates were obtained with the estradiol + tamoxifen-treated rats and these levels were significantly greater than those from animals receiving only tamoxifen. Similarly, maximally amphetamine-stimulated responses were obtained from estradiol + tamoxifen-treated rats, however, in contrast to potassium, these values were significantly greater than both animals receiving either estradiol or tamoxifen alone. These data demonstrate that the nigrostriatal dopaminergic system appears particularly sensitive to the modulatory effects of a combined treatment with estradiol + tamoxifen. Moreover, some of the potential mechanisms of these responses are indicated by the differential dopamine outputs as evoked by potassium or amphetamine. The significance of these synergistic actions is their potential to mimic changes that may occur under conditions of tamoxifen treatment of premenopausal women as has been suggested for women at risk for breast cancer.
McDermott J L; Anderson L I; Dluzen D E
Neuroendocrinology
1997
1997-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1159/000127236" target="_blank" rel="noreferrer noopener">10.1159/000127236</a>
Obesity-associated decrease in growth hormone-releasing hormone gene expression: a mechanism for reduced growth hormone mRNA levels in genetically obese Zucker rats.
*Gene Expression; Animals; Blotting; Growth Hormone-Releasing Hormone/*genetics; Growth Hormone/blood/*genetics/metabolism; Male; Messenger/*metabolism; Northern; Obesity/*metabolism; Pituitary Gland/metabolism; Rats; RNA; Zucker
The secretion of growth hormone (GH) is impaired in the genetically obese Zucker rat where GH gene expression and plasma GH levels are depressed; however, the underlying mechanism of this abnormality remains unclear. We have evaluated the potential causative role of hypothalamic GH-releasing hormone (GHRH) and somatostatin (SRIH) gene expression in the onset of the decreased GH mRNA levels by studying both GHRH and SRIH mRNA and peptide levels in obese and lean rats at 5 weeks of age when the decrease in GH mRNA is first detected. At that age both GHRH content and GHRH mRNA were significantly reduced in obese rats as compared to lean controls; hypothalamic SRIH content was also decreased in obese rats, but SRIH mRNA levels did not differ. Since GHRH is capable of stimulating GH gene expression, the decreased GHRH mRNA level could be a critical factor in causing the attenuation in GH gene expression and consequent diminution of circulating plasma GH.
Ahmad I; Finkelstein J A; Downs T R; Frohman L A
Neuroendocrinology
1993
1993-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1159/000126558" target="_blank" rel="noreferrer noopener">10.1159/000126558</a>
Sex differences in methamphetamine-evoked striatal dopamine output are abolished following gonadectomy: comparisons with potassium-evoked output and responses in prepubertal mice.
Animals; Dopamine Uptake Inhibitors/*pharmacology; Dopamine/*metabolism; Female; In Vitro Techniques; Male; Methamphetamine/*pharmacology; Mice; Neostriatum/drug effects/*metabolism; Orchiectomy; Ovariectomy; Potassium/*pharmacology; Sex Characteristics; Sexual Maturation
Sex differences are reported for methamphetamine (MA)-induced neurotoxicity of the nigrostriatal dopaminergic system. In an attempt to understand some of the bases for these differences, we investigated MA-evoked dopamine (DA) responses from superfused striatal tissue fragments of intact and male and female CD-1 mice. These responses were compared with that of gonadectomized mice, potassium-evoked DA responses in intact mice and responses in prepubertal mice. In experiment 1, DA responses were tested using infusion of MA at doses of 1, 10, 100 and 1,000 microM. In intact mice, mean peak MA-evoked DA responses were consistently increased and significantly greater in male vs. female mice at the 1,000 microM dose. No such significant differences were observed between gonadectomized male vs. female mice (experiment 2). In contrast to MA, potassium-stimulated DA responses were increased in intact female mice, with statistically significant differences at doses of 30 and 60 mM (experiment 3). No statistically significant differences between intact prepubertal male and female mice were obtained in response to a 1,000 microM dose of MA (experiment 4) or to a 60 mM dose of potassium (experiment 5). These results indicate that intact male mice show greater sensitivity to MA-evoked DA output. This sex difference is abolished following gonadectomy, is not observed with potassium, nor is it present in prepubertal mice. The increased sensitivity to MA shown by intact males may be related to the greater degree of striatal dopaminergic neurotoxicity observed in male mice in response to this psychostimulant and appears to be attributable to differences in gonadal steroid hormones between male and female mice.
Dluzen Dean E; Salvaterra Ty J
Neuroendocrinology
2005
2005
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1159/000090983" target="_blank" rel="noreferrer noopener">10.1159/000090983</a>