Cellular and Molecular Neurobiology

, Volume 16, Issue 3, pp 325–344 | Cite as

Estrogen control of central neurotransmission: Effect on mood, mental state, and memory

  • George Fink
  • Barbara E. H. Sumner
  • Roberta Rosie
  • Oliver Grace
  • John P. Quinn


1. Estrogen exerts profound effects on mood, mental state and memory by acting on both “classical” monoamine and neuropeptide transmitter mechanisms in brain. Here we review an example of each type of action.

2. With respect to the effect of estrogen on central monoamine neurotransmission, low levels of estrogen in women are associated with the premenstrual syndrome, postnatal depression and post-menopausal depression. Sex differences in schizophrenia have also been attributed to estrogen. Previous studies have shown that estrogen stimulates a significant increase in dopamine2 (D2) receptors in the striatum. Here we show for the first time that estrogen also stimulates a significant increase in the density of 5-hydroxytryptamine2A (5-HT2A) binding sites in anterior frontal, cingulate and primary olfactory cortex and in the nucleus accumbens, areas of the brain concerned with the control of mood, mental state, cognition, emotion and behavior. These findings explain, for example, the efficacy of estrogen therapy or 5-HT uptake blockers such as fluoxetine in treating the depressive symptoms of the premenstrual syndrome, and suggest that the sex differences in schizophrenia may also be due to an action of estrogen mediated by way of 5-HT2A receptors.

3. With respect to the effect of estrogen on central neuropeptide transmission, estrogen stimulates the expression of the arginine vasopressin (AVP) gene in the bed nucleus of the stria terminalis (BNST) in rodents. This results in a 100-fold increase in AVP mRNA in the BNST and a massive increase in AVP peptide in the BNST and its projections to the lateral septum and lateral habenula. The BNST-AVP system enhances and/or maintains “social” or “olfactory” memory, and thus provides a powerful model for correlating transcriptional control of neuropeptide gene expression with behavior. Whether similar mechanisms operate in the human remain to be determined.

4. These two examples of the action of estrogen on central neurotransmission are discussed in terms of their immediate clinical importance for the treatment of depressive symptoms, their use as powerful models for investigations on the steroid control of central neurotransmitter mechanisms, and the role of estrogen as “Nature's” psychoprotectant.

Key words

estrogen as psychoprotectant estradiol-17ß testosterone aromatase serotonin 5-hydroxytryptamine 5-hydroxytryptamine2 receptors cerebral cortex nucleus accumbens arginine vasopressin bed nucleus of the stria terminalis social memory psychosis depression premenstrual syndrome postnatal depression schizophrenia mania Tourette's syndrome 


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  1. Aghajanian, G. K., Sprouse, J. S., and Rasmussen, K. (1987). Physiology of the midbrain serotonin system. InPsychopharmacology: The Third Generation of Progress (H. Y. Meltzer, Ed.). Raven Press, New York, pp. 141–149.Google Scholar
  2. Angermeyer, M. C., Kühn, L., and Goldstein, J. M. (1990). Gender and the course of schizophrenia: Differences in treated outcomes.Schizophr. Bull. 16293–307.PubMedGoogle Scholar
  3. Appel, N. M., Mitchell, W. M., Garlick, R. K., Glennon, R. A., Teitler, M., and De Souza, E. B. (1990). Autoradiographic characterization of (±)-1-(2.5-dimethoxy-4-[125l]iodophenyl)-2-aminopropane ([125l]DOI) binding to 5-HT2 and 5-HT1C receptors in rat brain.J. Pharmacol. Exp. Ther. 255843–857.PubMedGoogle Scholar
  4. Ashcroft, G. W., Eccleston, D., Murray, L. G., Glen, A. I. M., Crawford, T. B. B., Pullar, I. A., Shields, P. J., Walter, D. S., Blackburn, I. M., Connechan, J., and Lonergan, M. (1972). Modified amine hypothesis for the aetiology of affective illness.Lancet 3573–577.Google Scholar
  5. Bleuler, E. (1950).Dementia Praecox or the Group of Schizophrenias International Universities Press, New York.Google Scholar
  6. Blue, M. E., Yagaloff, K. A., Mamounas, L. A., Hartig, P. R., and Molliver, M. E. (1988). Correspondence between 5-HT2 receptors and serotonergic axons in rat neocortex.Brain Res. 453315–328.PubMedGoogle Scholar
  7. Bluthé, R.-M., Gheusi, G., and Dantzer, R. (1993a). Gonadal steroids influence the involvement of arginine vasopressin in social recognition in mice.Psychoneuroendocrinology 18323–335.PubMedGoogle Scholar
  8. Bluthé, R. M., Suarez, S., Fink, G., Roques, B., and Dantzer, R. (1993b). Social recognition in mice is modulated by androgen-dependent vasopressinergic and cholecystokininergic neurotransmission. Proceedings of the Society for Neuroscience 23rd Annual Meeting, Washington, DC. p. 73.6.Google Scholar
  9. Chiodo, L. A., and Caggiula, A. R. (1983). Substantia nigra dopamine neurons: Alterations in basal discharge rates and autoreceptor sensitivity induced by estrogen.Neuropharmacology 22593–599.PubMedGoogle Scholar
  10. Cone, R. I., Davis, G. A., and Coy, R. W. (1981). Effects of ovarian steroids on serotonin metabolism within grossly dissected and microdissected brain regions of the ovariectomized rat.Brain Res. Bull. 7639–644.PubMedGoogle Scholar
  11. Cookson, J. C. (1985). The neuroendocrinology of mania.J. Affect. Disord. 8233–241.PubMedGoogle Scholar
  12. Dalton, K. (1959). Menstruation and acute psychiatric illnesses.Br. Med. J. 1148–149.Google Scholar
  13. Dantzer, R., and Bluthé, R.-M. (1992). Vasopressin involvement in antipyresis, social communication and social recognition: A synthesis.Crit. Rev. Neurobiol. 6243–255.PubMedGoogle Scholar
  14. Dantzer, R., Koob, G. F., Bluthé, R.-M., and Le Moal, M. (1988). Septal vasopressin modulates social memory in male rats.Brain Res. 457143–147.PubMedGoogle Scholar
  15. Dean, C., and Kendell, R. E. (1981). The symptomatology of puerperal illnesses.Br. J. Psychiatry 139128–133.PubMedGoogle Scholar
  16. De Vries, G. J., Duetz, W., Buijs, R. M., van Heerikhuize, J., and Vreeburg, J. T. M. (1986). Effects of androgens and estrogens on the vasopressin and oxytocin innervation of the adult rat brain.Brain Res. 399296–302.PubMedGoogle Scholar
  17. Di Paolo, T. (1994). Modulation of brain dopamine transmission by sex steroids.Rev. Neurosci. 527–42.PubMedGoogle Scholar
  18. Dow, R. C., Williams, B. C., Bennie, J., Carroll, S., and Fink, G. (1994). A central 5-HT2 receptor mechanism plays a key role in the proestrous surge of luteinizing hormone but not prolactin in the rat.Psychoneuroendocrinology 19395–399.PubMedGoogle Scholar
  19. Duinkerke, S. J., Botter, P. A., Jansen, A. A. I., van Dongen, P. A. M., van Haaften, A. J., Boom, A. J., van Laarhoven, J. H. M., and Busard, H. L. S. M. (1993). Ritanserin, a selective 5-HT(2/1C) antagonist, and negative symptoms in schizophrenia. A placebo-controlled double-blind trial.Br. J. Psychiatry 163451–455.PubMedGoogle Scholar
  20. Edwards, J. G. (1994). Risperidone for schizophrenia.Br. Med. J. 3081311–1312.Google Scholar
  21. Everett, J. W. (1988). Pituitary and hypothalamus: Perspectives and overviews. InThe Physiology of Reproduction (E. Knobil and J. Neil, Eds.), Raven Press, New York, pp. 1143–1159.Google Scholar
  22. Fink, G. (1979). Neuroendocrine control of gonadotrophin secretion.Br. Med. Bull. 35155–160.PubMedGoogle Scholar
  23. Fink, G. (1988). The G. W. Harris Lecture. Steroid control of brain and pituitary function.Q. J. Exp. Physiol. 73257–293.PubMedGoogle Scholar
  24. Fink, G. (1994). Molecular principles from neuroendocrine models: Steroid control of central neurotransmission. InProgress in Brain Research—Neuroscience: From the Molecular to the Cognitive (F. Bloom, Ed.), Elsevier, Amsterdam, pp. 139–147.Google Scholar
  25. Fink, G. (1995). The self-priming effect of LHRH; A unique servomechanism and possible cellular model for memory.Front. Neuroendocrinol. 161–8.PubMedGoogle Scholar
  26. Friedhoff, A. J. (1986). Insights into the pathophysiology and pathogenesis of Gilles de la Tourette syndrome.Rev. Neurol. 142860–864.PubMedGoogle Scholar
  27. Hackmann, E., Wirz-Justice, A., and Lichtsteiner, M. (1973). The uptake of dopamine and serotonin in rat brain during progesterone decline.Psychopharmacologia 32183–191.PubMedGoogle Scholar
  28. Häfner, H., Riecher-Rössler, A., An Der Heiden, W., Maurer, K., Fätkenheuer, B., and Löffler, W. (1993). Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia.Psychol. Med. 23925–940.PubMedGoogle Scholar
  29. Hoyer, D., Clarke, D. E., Fozard, J. R., Hartig, P. R., Martin, G. R., Mylecharane, E. J., Saxena, P. R., and Humphrey, P. P. A. (1994). VII. International Union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin).Pharmacol. Rev. 46157–203.PubMedGoogle Scholar
  30. Hunter, A. J., Hole, D. R., and Wilson, C. A. (1985). Studies into the dual effects of serotonergic pharmacological agents on female sexual behaviour in the rat: Preliminary evidence that endogenous 5-HT is stimulatory.Pharmacol. Biochem. Behav. 225–13.PubMedGoogle Scholar
  31. James, M. D., Lane, S. M., Hole, D. R., and Wilson, C. A. (1989). Hypothalamic sites of action of the dual effect of 5-HT on female sexual behaviour in the rat. InBehavioral Pharmacology of 5-HT (P. Bevan, A. R. Cools, and T. Archer, Eds.), Lawrence Erlbaum Associates, Hillsdale, NJ, pp. 73–77.Google Scholar
  32. Janssen, P. A. J., Niemegeers, C. J. E., Awouters, F., Schellekens, K. H. L., Megens, A. A. H. P., and Meert, T. F. (1988). Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties.J. Pharmacol. Exp. Ther. 244685–693.PubMedGoogle Scholar
  33. Kaplan, H. I., and Sadock, B. J. (1985).Comprehensive Textbook of Psychiatry Williams and Wilkins, Baltimore, MD.Google Scholar
  34. Klaiber, E. L., Broverman, D. M., Vogel, W., and Kobayashi, Y. (1979). Estrogen therapy for severe persistent depressions in women.Arch. Gen. Psychiatry 36550–554.PubMedGoogle Scholar
  35. Kraepelin, E. (1971).Dementia Praecox and Paraphrenia Krieger, Huntington, NY.Google Scholar
  36. Ladisich, W. (1977). Influence of progesterone on serotonin metabolism: A possible causal factor for mood changes.Psychoneuroendocrinology 2257–266.PubMedGoogle Scholar
  37. Laruelle, M., Abi-Dargham, A., Casanova, M. F., Toti, R., Weinberger, D. R., and Kleinman, J. E. (1993). Selective abnormalities of prefrontal serotonergic receptors in schizophrenia.Arch. Gen. Psychiatry 50810–818.PubMedGoogle Scholar
  38. Leckman, J. F., and Scahill, L. (1990). Possible exacerbation of tics by androgenic steroids.N. Engl. J. Med. 3221674.Google Scholar
  39. Lévesque, D., Gagné, B., Barden, N., and Di Paolo, T. (1992). Chronic estradiol treatment increases anterior pituitary but not striatall D2 dopamine receptor mRNA levels in rats.Neurosci. Lett. 1405–8.PubMedGoogle Scholar
  40. Levy, A. D., Baumann, M. H., and Van de Kar, L. D. (1994). Review of the influence of cocaine on the monoaminergic regulation of neuroendocrine function.Front. Neuroendocrinol. 1585–156.PubMedGoogle Scholar
  41. Lewis, S. (1992). Sex and schizophrenia: Vive la différence.Br. J. Psychiatry 161445–450.PubMedGoogle Scholar
  42. Leysen, J. E., Van Gompel, P., Verwimp, M., and Niemegeers, C. J. E. (1983). Role and localisation of serotonin (S2)-receptor binding sites: Effects of neuronal lesions. InCNS Receptors—From Molecular Pharmacology to Behaviour (P. Mandel and F. V. de Feudis, Eds.), Raven Press, New York, pp. 373–383.Google Scholar
  43. Leysen, J. E., Janssen, P. M. F., Gommeren, W., Wynants, J., Pauwels, P. J., and Janssen, P. A. J. (1992).In vitro andin vivo receptor binding and effects on monoamine turnover in rat brain regions of the novel antipsychotics risperidone and ocaperidone.Mol. Pharmacol. 41494–508.PubMedGoogle Scholar
  44. Loranger, A. W. (1984). Sex difference in age at onset of schizophrenia.Arch. Gen. Psychiatry 41157–161.PubMedGoogle Scholar
  45. MacKinnon, P. C. B., and MacKinnon, I. L. (1956). Hazards of the menstrual cycle.Br. Med. J. 1555.Google Scholar
  46. Mayes, C. R., Watts, A. G., McQueen, J. K., Fink, G., and Charlton, H. M. (1988). Gonadal steroids influence neurophysin II distribution in the forebrain of normal and mutant mice.Neuroscience 251013–1022.PubMedGoogle Scholar
  47. McEwen, B. S., Biegon, A., Rainbow, T. C., Paden, C., Snyder, L., and DeGroff, V. (1981). The interaction of estrogens with intracellular receptors and with putative neurotransmitter receptors: Implications for the mechanisms of activation of regulation of sexual behavior and ovulation. InSteroid Hormone Regulation of the Brain (K. Fuxe, J. A. Gustafsson, and L. Wetterberg, Ed.), Pergamon, New York, pp. 15–29.Google Scholar
  48. Meltzer, H. Y., Matsubara, S., and Lee, J.-C. (1989). Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pK1 values.J. Pharmacol. Exp. Ther. 251238–246.PubMedGoogle Scholar
  49. Mendelson, S. D., and Gorzalka, B. B. (1986). Serotonin type 2 antagonists inhibit lordosis behaviour in the female rat: Reversal with quipazine.Life Sci. 3833–39.PubMedGoogle Scholar
  50. Mengod, G., Pompeiano, M., Martinez-Mir, M. I., and Palacios, J. M. (1990). Localization of the mRNA for the 5-HT2 receptor byin situ hybridization histochemistry. Correlation with the distribution of receptor sites.Brain Res. 524139–143.PubMedGoogle Scholar
  51. Miller, M. A., Urban, J. H., and Dorsa, D. M. (1989). Steroid dependency of vasopressin neurons in the bed nucleus of the stria terminalis byin situ hybridization.Endocrinology 1252335–2340.PubMedGoogle Scholar
  52. Mohr, E., and Richter, D. (1990). Sequence analysis of the promoter region of the rat vasopressin gene.FEBS Lett. 260305–308.PubMedGoogle Scholar
  53. Morilak, D. A., Garlow, S. J., and Ciaranello, R. D. (1993). Immunocytochemical localization and description of neurons expressing serotonin2 receptors in the rat brain.Neuroscience 54701–717.PubMedGoogle Scholar
  54. Naftolin, F., Ryan, K. J., Davies, I. J., Reddy, V. V., Flores, F., Petro, Z., Kuhn, M., White, R. J., Takoaka, Y., and Wolin, L. (1975). The formation of estrogens by central neuroendocrine tissues.Recent Prog. Horm. Res. 31295–315.PubMedGoogle Scholar
  55. Nauta, W. J. H. (1963). Central nervous organization and the endocrine motor system. InAdvances in Neuroendocrinology (A. V. Nalbandov, Ed.), University of Illinois Press, Urbana, pp. 5–12.Google Scholar
  56. O'Brien, P. M. S. (1993). Helping women with premenstrual syndrome.Br. Med. J. 3071471–1475.Google Scholar
  57. Palacios, J. M., Waeber, C., Hoyer, D., and Mengod, G. (1990). Distribution of serotonin receptors.Ann. N.Y. Acad. Sci. 60036–52.PubMedGoogle Scholar
  58. Pauls, D. L., and Leckman, J. F. (1986). The inheritance of Gilles de la Tourette's syndrome and associated behaviors.N. Engl. J. Med. 315993–997.PubMedGoogle Scholar
  59. Pazos, A., Cortés, R., and Palacios, J. M. (1985). Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. Serotonin-2 receptors.Brain Res. 346231–249.PubMedGoogle Scholar
  60. Pfaff, D. W. (1980).Estrogens and Brain Function Springer, New York.Google Scholar
  61. Pompeiano, M., Palacios, J. M., and Mengod, G. (1994). Distribution of the serotonin 5-HT2 receptor family mRNAs: Comparison between 5-HT2A and 5-HT2C receptors.Mol. Brain Res. 23163–178.PubMedGoogle Scholar
  62. Pope, H. G. J., and Katz, D. L. (1988). Affective and psychotic symptoms associated with anabolic steroid use.Am. J. Psychiatry 145487–490.PubMedGoogle Scholar
  63. Rapkin, A. J. (1992). The role of serotonin in premenstrual syndrome.Clin. Obstet. Gynecol. 35629–636.PubMedGoogle Scholar
  64. Reid, R. L., and Yen, S. S. C. (1981). Premenstrual syndrome.Am. J. Obstet. Gynecol. 13985–104.PubMedGoogle Scholar
  65. Riecher-Rössler, A., and Häfner, H. (1993). Schizophrenia and oestrogens—Is there an association?Eur. Arch. Psychiatry Clin. Neurosci. 242323–328.PubMedGoogle Scholar
  66. Rosie, R., Wilson, H., and Fink, G. (1993). Testosterone induces an all-or-none, exponential increase in arginine vasopressin mRNA in the bed nucleus of stria terminalis of thehypogonadal mouse.Mol. Cell. Neurosci. 4121–126.Google Scholar
  67. Sarkar, D. K., and Fink, G. (1981). Gonadotropin-releasing hormone surge: possible modulation through postsynaptic α-adrenoreceptors and two pharmacologically distinct dopamine receptors.Endocrinology 108862–867.PubMedGoogle Scholar
  68. Seeman, M. V., and Lang, M. (1990). The role of estrogens in schizophrenia gender differences.Schizophr. Bull. 16185–195.PubMedGoogle Scholar
  69. Seeman, P. (1992). Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4.Neuropsychopharmacology 7261–284.PubMedGoogle Scholar
  70. Sheldon, P. W., and Aghajanian, G. K. (1990). Serotonin (5-HT) induces IPSPs in pyramidal layer cells of rat piriform cortex: Evidence for the involvement of a 5-HT2-activated interneuron.Brain Res. 50662–69.PubMedGoogle Scholar
  71. Shimizu, H., and Bray, G. A. (1993). Effects of castration, estrogen replacement and estrus cycle on monoamine metabolism in the nucleus-accumbens, measured by microdialysis.Brain Res. 621200–206.PubMedGoogle Scholar
  72. Strange, P. G. (1994). Dopamine D4 receptors: curioser and curioser.Trends Phamacol. Sci. 15317–319.Google Scholar
  73. Studd, J., and Zamblera, D. (1994). Premenstrual depression.Focus Depress. 26–9.Google Scholar
  74. Sumner, B. E. H., and Fink, G. (1993). Effects of acute estradiol on 5-hydroxytryptamine and dopamine receptor subtype mRNA expression in female rat brain.Mol. Cell. Neurosci. 483–92.Google Scholar
  75. Sumner, B. E. H., and Fink, G. (1995a). Estrogen increases the density of 5-HT2A receptors in cerebral cortex and nucleus accumbens in the female rat.J. Steroid Biochem. Mol. Biol. 545–20.Google Scholar
  76. Sumner, B. E. H., and Fink, G. (1995b). Oestradiol-17ß in its positive feedback mode significantly increases 5-HT2A receptor density in the frontal, cingulate and piriform cortex of the female rat.J. Physiol. 483.P:52P.Google Scholar
  77. Sumner, B. E. H., Rosie, R., and Fink, G. (1992). Relative density of 5-hydroxytryptamine receptor subtype mRNAs in female rat neuroendocrine brain determined byin situ hybridization histochemistry.Mol. Cell. Neurosci. 3215–223.Google Scholar
  78. Tansey, E. M., Arbuthnott, G. W., Fink, G., and Whale, D. (1983). Oestradiol-17ß increases the firing rate of antidromically identified neurones of the rat neostriatum.Neuroendocrinology 37106–110.PubMedGoogle Scholar
  79. Therrien, M., and Drouin, J. (1993). Cell-specific helix-loop-helix factor required for pituitary expression of the pro-opiomelanocortin gene.Mol. Cell. Biol. 132342–2353.PubMedGoogle Scholar
  80. Weiner, R. I., and Ganong, W. F. (1978). Role of brain monoamines and histamine in regulation of anterior pituitary secretion.Physiol. Rev. 58905–976.PubMedGoogle Scholar
  81. Wieck, A., Kumar, R., Hirst, A. D., Marks, M. N., Campbell, I. C., and Checkley, S. A. (1991). Increased sensitivity of dopamine receptors and recurrence of affective psychosis after childbirth.Br. Med. J. 303613–616.Google Scholar
  82. Wilson, J. D., and Foster, D. W. (Eds.) (1992).Williams Textbook of Endocrinology 8th ed., W B Saunders, Philadelphia, 1712.Google Scholar
  83. Wood, S. H., Mortola, J. F., Chan, Y. F., Moossazadeh, F., and Yen, S. S. C. (1992). Treatment of premenstrual syndrome with fluoxetine: A double-blind, placebo-controlled, crossover study.Obstet. Gynecol. 80339–344.PubMedGoogle Scholar
  84. Wright, W. E. (1992). Muscle basic helix-loop-helix proteins and the regulation of myogenesis.Curr. Opin. Gen. Dev. 2243–248.Google Scholar
  85. Yoon, S. O., and Chikaraishi, D. M. (1992). Tissue-specific transcription of the rat tyrosine hydroxylase gene requires synergy between an AP-1 motif and an overlapping E box-containing dyad.Neuron 955–67.PubMedGoogle Scholar
  86. Zahm, D. S., and Brog, J. S. (1992). On the significance of subterritories in the “accumbens” part of the rat ventral striatum.Neuroscience 50751–767.PubMedGoogle Scholar
  87. Zifa, E., and Fillion, G. (1992). 5-hydroxytryptamine receptors.Pharmacol. Rev. 44401–458.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • George Fink
    • 1
  • Barbara E. H. Sumner
    • 1
  • Roberta Rosie
    • 1
  • Oliver Grace
    • 1
  • John P. Quinn
    • 1
  1. 1.MRC Brain Metabolism UnitUniversity Department of PharmacologyEdinburghUK

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