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 µg 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-µg 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-µg 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 µg. No statistically significant effects upon uterine weights were obtained for any of the doses of TMX tested. Behaviorally, TMX at 500 µg 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.

Keywords:
Neurodegeneration, Catecholamines, Neuroprotection, Parkinson’s disease, Selective estrogen receptor modulators, Methamphetamine, Mice
1.
Diamond SG, Markham CH, Hoehn MM, McDowell FH, Meunter MD: An examination of male-female differences in progression and mortality of Parkinson’s disease. Neurology 1990;40:763–766.
2.
Dluzen DE, Disshon KA, McDermott JL: Estrogen as a modulator of striatal dopaminergic neurotoxicity; in Marwah J, Teitelbaum H (eds): Recent Advances in Neurodegenerative Disorders. Scottsdale, Prominent Press, 1998, vol 1, pp 149–192.
3.
Baldereschi M, Dicarlo A, Rocca A, Vanni P, Maggi S, Perissinotto E, Grigoletto F, Amaducci L, Inzitari D, for the ILSA Working Group: Parkinson’s disease and parkinsonism in a longitudinal study. Two-fold higher incidence in men. Neurology 2000;55:1358–1363.
4.
Schrag A, Ben-Shlomo Y, Quinn NP: Cross-sectional prevalence survey of idiopathic Parkinson’s disease and parkinsonism in London. Br Med J 2001;321:21–22.
5.
Swerdlow RH, Parker WD, Currie LJ, Bennet JP, Harrison MB, Trugman JM, Wooten GF: Gender ratio differences between Parkinson’s disease patients and their affected relatives. Parkinsonism Relat Disord 2001;7:129–136.
6.
Toung TJ, Traystman RJ, Hurn PD: Estrogen-mediated neuroprotection after experimental strokes in male rats. Stroke 1998;29:1666–1670.
7.
Fukuda K, Yao H, Ibayashi S, Nakahara T, Uchimura H, Fujishima M, Hall ED: Ovariectomy exacerbates and estrogen replacement attenuates phototrombotic focal ischemic brain injury in rats. Stroke 2000;31:155–160.
8.
Liao S, Chen W, Kuo J, Chen C: Association of serum estrogen level and ischemic neuroprotection in female rats. Neurosci Lett 2001;297:159–166.
9.
Wise PM, Dubal DB, Wilson ME, Rau SW, Bottner M, Rosewell KL: Estradiol is a protective factor in the adult and aging brain: Understanding of mechanisms derived from in vivo and in vitro studies. Brain Res Rev 2001;37:313–319.
10.
Granholm AC: Oestrogen and nerve growth factor – neuroprotection and repair in Alzheimer’s disease. Expert Opin Invest drugs 2000;9:685–694.
11.
Miller MM, Monjan AA, Buckholtz NS: Estrogen replacement therapy for the potential treatment or prevention of Alzheimer’s disease. Ann NY Acad Sci 2001;949:223–234.
12.
Owens CT: Estrogen replacement therapy for Alzheimer’s disease in postmenopausal women. Ann Pharmacother 2002;37:1273–1281.
13.
Dluzen DE, McDermott JL, Liu B: Estrogen alters MPTP-induced neurotoxicity in female mice: Effects on striatal dopamine concentrations and release. J Neurochem 1996;66:658–666.
14.
Dluzen DE, McDermott JL, Liu B: Estrogen as a neuroprotectant against MPTP-induced neurotoxicity in C57/Bl mice. Neurotoxicol Teratol 1996;18:603–606.
15.
Miller D, Ali SF, O’Callaghan JP, Laws SC: The impact of gender and estrogen on striatal dopamine neurotoxicity. Ann NY Acad Sci 1998;844:153–165.
16.
Grandbois M, Morissette M, Callier S, Di Paolo T: Ovarian steroids and raloxifene prevent MPTP-induced dopamine depletion in mice. NeuroReport 2000;11:343–346.
17.
Callier S, Morissette M, Grandbois M, Pelaprat D, Di Paolo T: Neuroprotective properties of 17beta-estradiol, progesterone and raloxifene in MPTP C57Bl/6 mice. Synapse 2001;41:131–138.
18.
Tomas-Camardiel M, Sanchez-Hidalgo MC, Sanchez Del Pino MJ, Navarro A, Machado A, Cano J: Comparative study of the neuroprotective effect of dehydroepiandrosterone and 17β-estradiol against 1-methyl-4-phenylpyridium toxicity on rat striatum. Neuroscience 2002;109:569–584.
19.
Ramirez AD, Liu X, Menniti FS: Repeated estradiol treatment prevents MPTP-induced dopamine depletion in male mice. Neuroendocrinology 2003;77:223–231.
20.
Dluzen DE, McDermott JL: Neuroprotective role of estrogen upon methamphetamine and related neurotoxins within the nigrostriatal dopaminergic system. Ann NY Acad Sci 2000;914:112–126.
21.
Yu L, Liao P-C: Estrogen and progesterone distinctly modulate methamphetamine-induced dopamine and serotonin depletions in C57Bl/6J mice. J Neural Transm 2000;107:1139–1147.
22.
Gao X, Dluzen E: Tamoxifen abolishes estrogen’s neuroprotective effect upon methamphetamine neurotoxicity of the nigrostriatal dopaminergic system. Neuroscience 2001;103:385–394.
23.
Dluzen DE, McDermott JL: Estrogen, anti-estrogen and gender differences in methamphetamine neurotoxicity. Ann NY Acad Sci 2002;965:136–156.
24.
Yu L, Kuo Y, Cherng CG, Chen H-H, Hsu C-H: Ovarian hormones do not attenuate methamphetamine-induced dopaminergic neurotoxicity in mice gonadectomized at 4 weeks postpartum. Neuroendocrinology 2002;75:282–287.
25.
Dluzen DE: Estrogen decreases corpus striatal neurotoxicity in response to 6-hydroxydopamine. Brain Res 1997;767:340–344.
26.
Dluzen DE: Neuroprotective effects of estrogen upon the nigrostriatal dopaminergic system. J Neurocytol 2000;29:387–399.
27.
Dluzen E, McDermott JL: Gender differences in the neurotoxicity of the nigrostriatal dopaminergic system: Implications for Parkinson’s disease. J Gend Specif Med 2000;3:36–42.
28.
Dluzen DE, Horstink MWIM: Estrogen as a neuroprotectant of the nigrostriatal dopaminergic system: Laboratory and clinical considerations. Endocrine 2003;21:67–75.
29.
Horstink MWIM, Strijks E, Dluzen DE: Estrogen and Parkinson’s disease. Adv Neurol 2003;91:107–114.
30.
Dluzen DE, McDermott JL, Anderson LI: Tamoxifen eliminates estrogen’s neuroprotective effect upon MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system. Neurotoxicol Res 2001;3:291–300.
31.
Obata T, Kubota S: Protective effect of tamoxifen on 1-methyl-4-phenylpyridine-induced hydroxyl radical generation in the rat striatum. Neurosci Lett 2001;308:87–90.
32.
Dluzen DE, McDermott JL, Anderson LI: Tamoxifen diminishes methamphetamine-induced striatal dopamine depletion in intact female and male mice. J Neuroendocrin 2001;13:618–624.
33.
Gao X, Dluzen DE: The effect of testosterone upon methamphetamine neurotoxicity of the nigrostriatal dopaminergic system. Brain Res 2001;892:63–69.
34.
Gajjar M, Anderson LI, Dluzen DE: Acute effects of estrogen upon methamphetamine induced neurotoxicity of the nigrostriatal dopaminergic system. J Neural Transm 2003;110:1215–1224.
35.
McDermott JL, Anderson LI, Dluzen DE: Tamoxifen treatment of ovariectomized mice alters dopamine release from striatal tissue fragments superfused in vitro. Brain Res 1995;698:248–252.
36.
Dluzen DE, Anderson LI, Pilati CF: Methamphetamine-gonadal steroid hormone interactions: Effects upon acute toxicity and striatal dopamine depletions. Neurotoxicol Teratol 2002;24:267–273.
37.
Feder HH: Estrous cyclicity in mammals; in Adler NT (ed): Neuroendocrinology of Reproduction – Physiology and Behavior. New York, Plenum Press, 1981, pp 279–348.
38.
Vongher JM, Frye CA: Progesterone in conjunction with estradiol has neuroprotective effects in an animal model of neurodegeneration. Pharmacol Biochem Behav 1999;64:777–785.
39.
Yu L, Liao P-C: Sexual differences and estrous cycle in methamphetamine-induced dopamine and serotonin depletions in the striatum of mice. J Neural Transm 2000;107:419–427.
40.
Datla KP, Murray HE, Pillai A, Gillies GE, Dexter DT: Differences in dopaminergic neuroprotective effects of estrogen during estrous cycle. NeuroReport 2003;14:47–50.
41.
Myers RE, Anderson LI, Dluzen DE: Estrogen, but not testosterone, attenuates methamphetamine-evoked dopamine output from superfused striatal tissue of female and male mice. Neuropharmacology 2003;44:624–632.
42.
Cyr M, Calon F, Morissette M, Grandbois M, Di Paolo T, Callier S: Drugs with estrogen-like potency and brain activity: Potential therapeutic application for the CNS. Curr Pharm Res 2000;6:1287–1312.
43.
Landry M, Levesque D, Di Paolo T: Estrogenic properties of raloxifene, but not tamoxifen, on D2 and D3 dopamine receptors in rat forebrain. Neuroendocrinology 2002;76:214–222.
44.
Miller CC, Holmes PV, Edwards GL: Area postrema lesions elevate NPY levels and decrease anxiety-related behaviors in rats. Physiol Behav 2002;77:135–140.
45.
Sullivan GM, Apergis J, Gorman JM, LeDoux JE: Rodent doxapram model of panic attack: Behavioral effects and c-Fos immunoreactivity in the amygdala. Biol Psychiat 2003;53:863–870.
46.
Vendruscolo LF, Takahashi RN, Bruske GR, Ramos A: Evaluation of the anxiolytic-like effect of NKP608, a NK1-receptor antagonist, in two rat strains that differ in anxiety-related behaviors. Psychopharmacology 2003;170:287–293.
47.
Sato M, Rippy MK, Bryant U: Raloxifene, tamoxifen, nafoxidine or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J 1996;10:905–912.
48.
Kimelberg HK, Feustel PJ, Paquette J, Boulos A, Keller RW Jr, Tranmer BI: Acute treatment with tamoxifen reduces ischemic damage following cerebral artery occlusion. NeuroReport 2000;11:2675–2679.
49.
Dhandapani KM, Brann DW: Neuroprotective effects of estrogen and tamoxifen in vitro. Endocrine 2003;21:59–66.
50.
Kimelberg HK, Jin Y, Charniga C, Feustel PJ: Neuroprotective activity of tamoxifen in permanent focal ischemia. J Neurosurg 2003;99:138–142.
51.
Shy H, Malaiyandi L, Timiras P: Protective action of 17beta-estradiol and tamoxifen on glutamate toxicity in glial cells. Int J Develop Neurosci 2000;18:289–297.
52.
Hoyt KR, McLaughlin BA, Higgins DS Jr, Reynolds IJ: Inhibition of glutamate-induced mitochondrial depolarization by tamoxifen in cultured neurons. J Pharmacol Exp Ther 2000;293:480–486.
53.
Dluzen DE, McDermott JL: Gender differences in the neurotoxicity of the nigrostriatal dopaminergic system: Implications for Parkinson’s disease. J Gend Specif Med 2000;3:36–42.
54.
Dluzen DE, Tweed C, Anderson LI, Laping NJ: Gender differences in methamphetamine-induced mRNA associated with neurodegeneration in the mouse nigrostriatal dopaminergic system. Neuroendocrinology 2003;77:232–238.
© 2004 S. Karger AG, Basel
2004
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.