Abstract
Hormonal specificity of modulation of brain 5-HT2A receptors was investigated by comparing activity of compounds with varying effects on estrogen response in breast, bone, and uterus. A two-week estradiol treatment stimulated the decreased uterine weight of ovariectomized rats to intact rat values whereas an increase of 29% with tamoxifen and 16% with raloxifene was observed compared to vehicle-treated ovariectomized rats. In 18 assayed brain regions, ovariectomy decreased 5-HT2A receptor binding and mRNA levels in anterior cingulate and frontal cortices, striatum, and nucleus accumbens; estradiol restored this decrease to intact rat values. Dehydroepiandrosterone (DHEA) increased ovariectomized rats 5-HT2A receptor expression only in striatum and cortical amygdala. Tamoxifen increased 5-HT2A receptor density only in striatum. Raloxifene, an uterine estrogen receptor (ER) antagonist, increased, like estradiol, 5-HT2A receptor density and expression in cingulate and frontal cortices, striatum, and nucleus accumbens. Brain regional specificity of estradiol, DHEA, tamoxifen, and raloxifene on 5-HT2A receptors was observed which can be dissociated from peripheral activity.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Bethea CL, Pecins-Thompson M, Schutzer WE, Gundlah C, Lu ZN . (1998): Ovarian steroids and serotonin neural function. Mol Neurobiol 18: 87–123
Biegon A, Reches A, Snyder L, McEwen BS . (1983): Serotoninergic and noradrenergic receptors in the rat brain: Modulation by chronic exposure to ovarian hormones. Life Sci 32: 2015–2021
Bosse R, Di Paolo T . (1996): The modulation of brain dopamine and GABAA receptors by estradiol: A clue for CNS changes occurring at menopause. Cell Mol Neurobiol 16: 199–212
Charney DS . (1998): Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry 59: 11–14
Cyr M, Bosse R, Di Paolo T . (1998): Gonadal hormones modulate 5-hydroxytryptamine2A receptors: Emphasis on the rat frontal cortex. Neuroscience 83: 829–836
Cyr M, Ghribi O, Di Paolo T . (2000): Ovariectomy and gonadal modulation of glutamate levels and glutamate receptors of the NMDA and AMPA subtypes. J. Neuroendocrinol (in press).
Di Paolo T . (1994): Modulation of brain dopamine transmission by sex steroids. Rev Neurosci 5: 27–41
Du YL, Wilcox BD, Teitler M, Jeffrey JJ . (1994): Isolation and characterization of the rat 5-hydroxytryptamine type 2 receptor promoter: Constitutive and inducible activity in myometrial smooth muscle cells. Mol Pharmacol 45: 1125–1131
Fink G, Sumner BE . (1996): Oestrogen and mental state. Nature 383: 306
Fink G, Sumner BE, McQueen JK, Wilson H, Rosie R . (1998): Sex steroid control of mood, mental state and memory. Clin Exp Pharmacol Physiol 25: 764–775
Grese TA, Dodge JA . (1998): Selective estrogen receptor modulators (SERMs). Curr Pharm Des 4: 71–92
Halbreich U . (1997): Role of estrogen in postmenopausal depression. Neurology 48: S16–S19
Heron DS, Shinitzky M, Hershkowitz M, Samuel D . (1980): Lipid fluidity markedly modulates the binding of serotonin to mouse brain membranes. Proc Natl Acad Sci USA 77: 7463–7467
Kapur S, Remington G . (1996): Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry 153: 466–476
Katzenellenbogen JA, O'Malley BW, Katzenellenbogen BS . (1996): Tripartite steroid hormone receptor pharmacology: Interaction with multiple effector sites as a basis for the cell- and promoter-specific action of these hormones. Mol Endocrinol 10: 119–131
Klaiber EL, Broverman DM, Vogel W, Kobayashi Y . (1979): Estrogen therapy for severe persistent depressions in women. Arch Gen Psychiatry 36: 550–554
Labrie C, Flamand M, Belanger A, Labrie F . (1996): High bioavailability of dehydroepiandrosterone administered percutaneously in the rat. J Endocrinol 150(Suppl):S107–S118
Laflamme N, Nappi RE, Drolet G, Labrie C, Rivest S . (1998): Expression and neuropeptidergic characterization of estrogen receptors (ERalpha and ERbeta) throughout the rat brain: anatomical evidence of distinct roles of each subtype. J Neurobiol 36: 357–378
Lieberman JA, Mailman RB, Duncan G, Sikich L, Chakos M, Nichols DE, Kraus JE . (1998): Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiatry 44: 1099–1117
Marek GJ, Aghajanian GK . (1998): The electrophysiology of prefrontal serotonin systems: Therapeutic implications for mood and psychosis. Biol Psychiatry 44: 1118–1127
Martel C, Labrie C, Belanger A, Gauthier S, Merand Y, Li X, Provencher L, Candas B, Labrie F . (1998): Comparison of the effects of the new orally active antiestrogen EM-800 with ICI 182 780 and toremifene on estrogen-sensitive parameters in the ovariectomized mouse. Endocrinology 139: 2486–2492
Mengod G, Pompeiano M, Martinez-Mir MI, Palacios JM . (1990): Localization of the mRNA for the 5-HT2 receptor by in situ hybridization histochemistry. Correlation with the distribution of receptor sites. Brain Res 524: 139–143
Paech K, Webb P, Kuiper GGJM, Nilsson S, Gustafsson J-A, Kushner PJ, Scanlan TS . (1997): Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 277: 1508–1510
Paige LA, Christensen DJ, Gron H, Norris JD, Gottlin EB, Padilla KM, Chang CY, Ballas LM, Hamilton PT, McDonnell DP, Fowlkes DM . (1999): Estrogen receptor (ER) modulators each induce distinct conformational changes in ER alpha and ER beta. Proc Natl Acad Sci USA 96: 3999–4004
Paxinos G, Watson C . (1998): The rat brain in stereotaxic coordinates. 4th ed. New York, Academic Press
Pritchett DB, Bach AW, Wozny M, Taleb O, Dal Toso R, Shih JC, Seeburg PH . (1988): Structure and functional expression of cloned rat serotonin 5HT-2 receptor. Embo J 7: 4135–4140
Sumner BEH, Fink G . (1993): Effects of acute estradiol on 5-hydroxytryptamine and dopamine receptor subtype mRNA expression in female rat brain. Molec Cell Neurosci 4: 83–92
Sumner BEH, Fink G . (1995): Estrogen increases the density of 5-hydroxytryptamine(2A) receptors in cerebral cortex and nucleus accumbens in the female rat. J Steroid Biochem Mol Biol 54: 15–20
Sumner BEH, Fink G . (1998): Testosterone as well as estrogen increases serotonin2A receptor mRNA and binding site densities in the male rat brain. Brain Res Mol Brain Res 59: 205–214
Truss M, Beato M . (1993): Steroid hormone receptors: Interaction with deoxyribonucleic acid and transcription factors. Endocr Rev 14: 459–479
Willner P . (1997): The dopamine hypothesis of schizophrenia: Current status, future prospects. Int Clin Psychopharmacol 12: 297–308
Zifa E, Fillion G . (1992): 5-Hydroxytryptamine receptors. Pharmacol Rev 44: 401–458
Acknowledgements
The authors are greatly indebted to Dr. Fernand Labrie for the generous gift of perfused rat brain slices from animals of the protocol URMAr 50–97 and raloxifene which was synthesized in the medicinal chemistry division of his laboratory. This research was supported by a grant from the Medical Research Council (MRC) of Canada to T.D.P.; M.C. and M.L. are holders of a MRC of Canada studentship.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cyr, M., Landry, M. & Di Paolo, T. Modulation by Estrogen-Receptor Directed Drugs of 5-Hydroxytryptamine-2A Receptors in Rat Brain. Neuropsychopharmacol 23, 69–78 (2000). https://doi.org/10.1016/S0893-133X(00)00085-3
Received:
Revised:
Accepted:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(00)00085-3
Keywords
This article is cited by
-
Berberine produces antidepressant-like effects in ovariectomized mice
Scientific Reports (2017)
-
Adjunctive selective estrogen receptor modulator increases neural activity in the hippocampus and inferior frontal gyrus during emotional face recognition in schizophrenia
Translational Psychiatry (2016)
-
Potential Role of Oestrogen Modulation in the Treatment of Neurocognitive Deficits in Schizophrenia
CNS Drugs (2016)
-
Neurocognitive, Neuroprotective, and Cardiometabolic Effects of Raloxifene: Potential for Improving Therapeutic Outcomes in Schizophrenia
CNS Drugs (2016)
-
DHEA Enhances Emotion Regulation Neurocircuits and Modulates Memory for Emotional Stimuli
Neuropsychopharmacology (2013)
