Skip to main content
Log in

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

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Summary

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • 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 

  • Angermeyer, M. C., Kühn, L., and Goldstein, J. M. (1990). Gender and the course of schizophrenia: Differences in treated outcomes.Schizophr. Bull. 16293–307.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • Bleuler, E. (1950).Dementia Praecox or the Group of Schizophrenias International Universities Press, New York.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Cookson, J. C. (1985). The neuroendocrinology of mania.J. Affect. Disord. 8233–241.

    PubMed  Google Scholar 

  • Dalton, K. (1959). Menstruation and acute psychiatric illnesses.Br. Med. J. 1148–149.

    Google Scholar 

  • Dantzer, R., and Bluthé, R.-M. (1992). Vasopressin involvement in antipyresis, social communication and social recognition: A synthesis.Crit. Rev. Neurobiol. 6243–255.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Dean, C., and Kendell, R. E. (1981). The symptomatology of puerperal illnesses.Br. J. Psychiatry 139128–133.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Di Paolo, T. (1994). Modulation of brain dopamine transmission by sex steroids.Rev. Neurosci. 527–42.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Edwards, J. G. (1994). Risperidone for schizophrenia.Br. Med. J. 3081311–1312.

    Google Scholar 

  • 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 

  • Fink, G. (1979). Neuroendocrine control of gonadotrophin secretion.Br. Med. Bull. 35155–160.

    PubMed  Google Scholar 

  • Fink, G. (1988). The G. W. Harris Lecture. Steroid control of brain and pituitary function.Q. J. Exp. Physiol. 73257–293.

    PubMed  Google Scholar 

  • 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 

  • Fink, G. (1995). The self-priming effect of LHRH; A unique servomechanism and possible cellular model for memory.Front. Neuroendocrinol. 161–8.

    PubMed  Google Scholar 

  • Friedhoff, A. J. (1986). Insights into the pathophysiology and pathogenesis of Gilles de la Tourette syndrome.Rev. Neurol. 142860–864.

    PubMed  Google Scholar 

  • Hackmann, E., Wirz-Justice, A., and Lichtsteiner, M. (1973). The uptake of dopamine and serotonin in rat brain during progesterone decline.Psychopharmacologia 32183–191.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • Kaplan, H. I., and Sadock, B. J. (1985).Comprehensive Textbook of Psychiatry Williams and Wilkins, Baltimore, MD.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Kraepelin, E. (1971).Dementia Praecox and Paraphrenia Krieger, Huntington, NY.

    Google Scholar 

  • Ladisich, W. (1977). Influence of progesterone on serotonin metabolism: A possible causal factor for mood changes.Psychoneuroendocrinology 2257–266.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Leckman, J. F., and Scahill, L. (1990). Possible exacerbation of tics by androgenic steroids.N. Engl. J. Med. 3221674.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Lewis, S. (1992). Sex and schizophrenia: Vive la différence.Br. J. Psychiatry 161445–450.

    PubMed  Google Scholar 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • Loranger, A. W. (1984). Sex difference in age at onset of schizophrenia.Arch. Gen. Psychiatry 41157–161.

    PubMed  Google Scholar 

  • MacKinnon, P. C. B., and MacKinnon, I. L. (1956). Hazards of the menstrual cycle.Br. Med. J. 1555.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Mohr, E., and Richter, D. (1990). Sequence analysis of the promoter region of the rat vasopressin gene.FEBS Lett. 260305–308.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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 

  • O'Brien, P. M. S. (1993). Helping women with premenstrual syndrome.Br. Med. J. 3071471–1475.

    Google Scholar 

  • Palacios, J. M., Waeber, C., Hoyer, D., and Mengod, G. (1990). Distribution of serotonin receptors.Ann. N.Y. Acad. Sci. 60036–52.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Pfaff, D. W. (1980).Estrogens and Brain Function Springer, New York.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Pope, H. G. J., and Katz, D. L. (1988). Affective and psychotic symptoms associated with anabolic steroid use.Am. J. Psychiatry 145487–490.

    PubMed  Google Scholar 

  • Rapkin, A. J. (1992). The role of serotonin in premenstrual syndrome.Clin. Obstet. Gynecol. 35629–636.

    PubMed  Google Scholar 

  • Reid, R. L., and Yen, S. S. C. (1981). Premenstrual syndrome.Am. J. Obstet. Gynecol. 13985–104.

    PubMed  Google Scholar 

  • Riecher-Rössler, A., and Häfner, H. (1993). Schizophrenia and oestrogens—Is there an association?Eur. Arch. Psychiatry Clin. Neurosci. 242323–328.

    PubMed  Google Scholar 

  • 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 

  • 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.

    PubMed  Google Scholar 

  • Seeman, M. V., and Lang, M. (1990). The role of estrogens in schizophrenia gender differences.Schizophr. Bull. 16185–195.

    PubMed  Google Scholar 

  • Seeman, P. (1992). Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4.Neuropsychopharmacology 7261–284.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Strange, P. G. (1994). Dopamine D4 receptors: curioser and curioser.Trends Phamacol. Sci. 15317–319.

    Google Scholar 

  • Studd, J., and Zamblera, D. (1994). Premenstrual depression.Focus Depress. 26–9.

    Google Scholar 

  • 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 

  • 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 

  • 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.

  • 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 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Weiner, R. I., and Ganong, W. F. (1978). Role of brain monoamines and histamine in regulation of anterior pituitary secretion.Physiol. Rev. 58905–976.

    PubMed  Google Scholar 

  • 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 

  • Wilson, J. D., and Foster, D. W. (Eds.) (1992).Williams Textbook of Endocrinology 8th ed., W B Saunders, Philadelphia, 1712.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Wright, W. E. (1992). Muscle basic helix-loop-helix proteins and the regulation of myogenesis.Curr. Opin. Gen. Dev. 2243–248.

    Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • 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.

    PubMed  Google Scholar 

  • Zifa, E., and Fillion, G. (1992). 5-hydroxytryptamine receptors.Pharmacol. Rev. 44401–458.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fink, G., Sumner, B.E.H., Rosie, R. et al. Estrogen control of central neurotransmission: Effect on mood, mental state, and memory. Cell Mol Neurobiol 16, 325–344 (1996). https://doi.org/10.1007/BF02088099

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02088099

Key words

Navigation