Central Effects of Estrogens and Reproductive Neuroendocrinology
Estrogenic Properties of Raloxifene, but Not Tamoxifen, on D2 and D3 Dopamine Receptors in the Rat ForebrainLandry M.a · Lévesque D.b · Di Paolo T.a
aMolecular Endocrinology and Oncology Research Center and Faculté de Pharmacie, bUnité de Neuroscience, Centre de Recherche du CHUQ and Département de Médecine, Faculté de Médecine, Université Laval, Sainte-Foy, Que., Canada
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The present study investigated the estrogenic specificity of the modulation of dopamine D2 and D3 receptors by comparing the effects of estradiol with tamoxifen or raloxifene. These compounds have estrogenic and/or antiestrogenic activity depending on the target tissue. Two weeks after ovariectomy of female rats, we observed a 60% decrease in the uterine weight, which was prevented by a replacement therapy of 2 weeks with 17β-estradiol. A tamoxifen or raloxifene treatment of 2 weeks increased uterine weights by 35 and 15%, respectively, but significantly less than estradiol treatment. Ovariectomy decreased dopamine D2 receptor specific binding (20%) in the dorsolateral part of the anterior striatum and these receptors were left unchanged in the other parts of the striatum as well as in the olfactory tubercle and the nucleus accumbens. 17β-Estradiol and raloxifene, but not tamoxifen treatment prevented this decrease. Ovariectomy left dopamine D3 receptor specific binding unchanged. However, estradiol and raloxifene treatment decreased dopamine D3 receptor binding in the islands of Calleja, the core and shell of the nucleus accumbens and the dorsal part of the anterior striatum, compared with ovariectomized rats. Our results show that raloxifene, but not tamoxifen, has an agonist estrogenic activity on dopamine receptors. Furthermore, estradiol and raloxifene have opposite effects on specific binding to dopamine D2 and D3 receptors.
© 2002 S. Karger AG, Basel
- McEwen BS, Alves SE: Estrogen actions in the central nervous system. Endocr Rev 1999;20:279–307.
- Kawata M: Roles of steroid hormones and their receptors in structural organization in the nervous system. Neurosci Res 1995;24:1–46.
- Simpkins JW, Singh M, Bishop J: The potential role for estrogen replacement therapy in the treatment of the cognitive decline and neurodegeneration associated with Alzheimer’s disease. Neurobiol Aging 1994;15:S195–S197.
- 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 Des 2000;6:1287–1312.
- Becker JB: Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol Biochem Behav 1999;64:803–812.
- Di Paolo T: Modulation of brain dopamine transmission by sex steroids. Rev Neurosci 1994;5:27–41.
- Van Hartesveldt C, Joyce JN: Effects of estrogen on the basal ganglia. Neurosci Biobehav Rev 1986;10:1–14.
- Sato M, Rippy MK, Bryant HU: Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J 1996;10:905–912.
- Levenson AS, Jordan VC: Selective oestrogen receptor modulation: Molecular pharmacology for the millennium. Eur J Cancer 1999;35:1974–1985.
- Cyr M, Thibault C, Morissette M, Landry M, Di Paolo T: Estrogen-like activity of tamoxifen and raloxifene on NMDA receptor binding and expression of its subunits in rat brain. Neuropsychopharmacology 2001;25:242–257.
- Cyr M, Morissette M, Landry M, Di Paolo T: Estrogenic activity of tamoxifen and raloxifene on rat brain AMPA receptors. Neuroreport 2001;12:535–539.
- Cyr M, Landry M, Di Paolo T: Modulation by estrogen-receptor directed drugs of 5-hydroxytryptamine-2A receptors in rat brain. Neuropsychopharmacology 2000;23:69–78.
- Luo S, Martel C, Sourla A, Gauthier S, Merand Y, Belanger A, Labrie C, Labrie F: Comparative effects of 28-day treatment with the new anti-estrogen EM-800 and tamoxifen on estrogen-sensitive parameters in intact mice. Int J Cancer 1997;73:381–391.
- Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, Cullinan GJ, Bendele R, Kauffman RF, Bensch WR, Frolik CA, Termine JD, Bryant HU: Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 1994;93:63–69.
Paxinos G, Watson C: The Rat Brain in Stereotaxic Coordinates, ed 4. San Diego, Academic Press, 1998.
- Tremblay M, Rouillard C, Lévesque D: Dopamine D3 receptor antisense administration reduces basal c-fos and NGFI-B mRNA levels in the rat forebrain. Synapse 1999;32:51–57.
- Lévesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott D, Morgat JL, Schwartz JC, Sokoloff P: Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci USA 1992;89:8155–8159.
- Joyce JN, Loeschen SK, Marshall JF: Dopamine D2 receptors in rat caudate-putamen: The lateral to medial gradient does not correspond to dopaminergic innervation. Brain Res 1985;338:209–218.
- Falardeau P, Di Paolo T: Regional effect of estradiol on rat caudate-putamen dopamine receptors: Lateral-medial differences. Neurosci Lett 1987;74:43–48.
- Neve KA, Altar CA, Wong CA, Marshall JF: Quantitative analysis of [3H]spiroperidol binding to rat forebrain sections: Plasticity of neostriatal dopamine receptors after nigrostriatal injury. Brain Res 1984;302:9–18.
- Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, Schwartz JC: Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: Comparison with dopamine D2 receptor mRNA. Brain Res 1991;564:203–219.
- Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC: Molecular cloning and characterization of a novel dopamine receptor D3 as a target for neuroleptics. Nature 1990;347:146–151.
- Lévesque D, Martres MP, Diaz J, Griffon N, Lammers CH, Sokoloff P, Schwartz JC: A paradoxical regulation of the dopamine D3 receptor expression suggests the involvement of an anterograde factor from dopamine neurons. Proc Natl Acad Sci USA 1995;92:1719–1723.
- Herroelen L, De Backer JP, Wilczak N, Flamez A, Vauquelin G, De Keyser J: Autoradiographic distribution of D3-type dopamine receptors in human brain using [3H]7-hydroxy-N,N-di-n-propyl-2-aminotetralin. Brain Res 1994;648:222–228.
- Levant B: The D3 dopamine receptor: Neurobiology and potential clinical relevance. Pharmacol Rev 1997;49:231–252.
- Lammers CH, D’Souza U, Qin ZH, Lee SH, Yajima S, Mouradian MM: Regulation of striatal dopamine receptors by estrogen. Synapse 1999;34:222–227.
- Cyr M, Ghribi O, Di Paolo T: Regional and selective effects of oestradiol and progesterone on NMDA and AMPA receptors in the rat brain. J Neuroendocrinol 2000;12:445–452.
- Laflamme N, Nappi RE, Drolet G, Labrie C, Rivest S: Expression and neuropeptidergic characterization of estrogen receptors (ERα and ERβ) throughout the rat brain: Anatomical evidence of distinct roles of each subtype. J Neurobiol 1998;36:357–378.
- Shughrue PJ, Lane MV, Merchenthaler I: Comparative distribution of estrogen receptor-α and -β mRNA in the rat central nervous system. J Comp Neurol 1997;388:507–525.
- Saville B, Wormke M, Wang F, Nguyen T, Enmark E, Kuiper G, Gustafsson JA, Safe S: Ligand-, cell-, and estrogen receptor subtype (α/β)-dependent activation at GC-rich (Sp1) promoter elements. J Biol Chem 2000;275:5379–5387.
- Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS: Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 1997;277:1508–1510.
- Jones PS, Parrott E, White IN: Activation of transcription by estrogen receptor α and β is cell type- and promoter-dependent. J Biol Chem 1999;274:32008–32014.
Minowa T, Minowa MT, Mouradian MM: Analysis of the promoter region of the rat D2 dopamine receptor gene. Biochemistry 1992;31:8389–8396.
- D’Souza UM, Wang W, Gao DQ, Kanda S, Lee G, Junn E, Hwang CK, Jose PA, Mouradian MM: Characterization of the 5′ flanking region of the rat D3 dopamine receptor gene. J Neurochem 2001;76:1736–1744.
- Lonard DM, Smith CL: Molecular perspectives on selective estrogen receptor modulators (SERMs): Progress in understanding their tissue-specific agonist and antagonist actions. Steroids 2002;67:15–24.
- Misiti S, Schomburg L, Yen PM, Chin WW: Expression and hormonal regulation of coactivator and corepressor genes. Endocrinology 1998;139:2493–2500.
- Schwartz JC, Diaz J, Pilon C, Sokoloff P: Possible implications of the dopamine D3 receptor in schizophrenia and antipsychotic drug actions. Brain Res Rev 2000;31:277–287.
- Joyce JN: Dopamine D3 receptor as a therapeutic target for antipsychotic and antiparkinsonian drugs. Pharmacol Ther 2001;90:231–259.
- Gurevich EV, Bordelon Y, Shapiro RM, Arnold SE, Gur RE, Joyce JN: Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. Arch Gen Psychiatry 1997;54:225–232.
- Joyce JN, Lexow N, Bird E, Winokur A: Organization of dopamine D1 and D2 receptors in human striatum: Receptor autoradiographic studies in Huntington’s disease and schizophrenia. Synapse 1988;2:546–557.
- Joyce JN, Gurevich EV: D3 receptors and the actions of neuroleptics in the ventral striatopallidal system of schizophrenics. Ann NY Acad Sci 1999;877:595–613.
- Joyce JN, Meador-Woodruff JH: Linking the family of D2 receptors to neuronal circuits in human brain: Insights into schizophrenia. Neuropsychopharmacology 1997;16:375–384.
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