Cellular and Molecular Neurobiology

, Volume 16, Issue 2, pp 199–212 | Cite as

The modulation of brain dopamine and GABAA receptors by estradiol: A clue for CNS changes occurring at menopause

  • Roger Bossé
  • Thérèse Di Paolo


1. Tardive dyskinesia is more important in postmenopausal women than men of comparable age and a peak of first episodes of schizophrenia is observed in postmenopausal women. The effect of ovariectomy (2 weeks or 3 months) in rats was investigated as a model of decreased gonadal function associated with menopause.

2. Frontal cortex D1 receptor density and affinity were similar in intact male compared to intact female rats and progressively decreased in density with time after ovariectomy, with no change of affinity. Striatal D1 and D2 receptors also decreased in density after ovariectomy for both receptor subtypes, with no change of affinity. Striatal D1 receptor density and affinity were similar in intact male and female rats, whereas the density of D2 receptors was higher in females. Treatment with estradiol for 2 weeks restored the D2 but not the D1 receptor changes.

3. In the substantia nigra pars reticulata, striatum, nucleus accumbens, and entopeduncular nucleus, a progressive increase in [3H]flunitrazepam specific binding associated with GABAA receptors was observed as a function of time following ovariectomy; this was corrected with estradiol treatment. In contrast, the opposite was observed for [3H] flunitrazepam binding in the globus pallidus, where ovariectomy decreased binding, which was corrected with estradiol replacement therapy.

4. Low prefrontal cortex dopamine activity with implications of D1 receptors in negative symptoms of schizophrenia is hypothesized. Furthermore, GABAergic overactivity in the internal globus pallidus-substantia nigra pars reticulata complex is hypothesized in tardive dyskinesia.

5. The present data suggest that gonadal hormone withdrawal by reducing brain dopamine receptors and producing an imbalance of GABAA receptors in the output pathways of the striatum may predispose to schizophrenia and dyskinesia.

Key words

dopamine receptors GABAA receptors striatum frontal cortex substantia nigra pars reticulata globus pallidus entopeduncular nucleus nucleus accumbens ovariectomy estradiol 


  1. Albin, R. L., Young, A. B., and Penney, J. B. (1989). The functional anatomy of basal ganglia disorders.Trends Neurosci. 12366–375.PubMedGoogle Scholar
  2. Angermeyer, M. C. (1982). The association between family atmosphere and hospital. Career of schizophrenic patients.Br. J. Psychiat. 1411–11.Google Scholar
  3. Angermeyer, M. C., and Kühn, L. (1988). Gender differences in age at onset of schizophrenia: An overview.Eur. Arch. Psychiatry Neurol. Sci. 237351–364.PubMedGoogle Scholar
  4. Angermeyer, M. C., Goldstein, J. M., and Kühn, L. (1989). Gender differences in schizophrenia: Rehospitalization and community survival.Psychol. Med. 19365–382.PubMedGoogle Scholar
  5. Bardenstein, K. K., and McGlashan, T. H. (1990). Gender differences in affective, schizoaffective, and schizophreniform disorders. A review.Schizo. Res. 3159–172.Google Scholar
  6. Bédard, P. J., and Boucher, R. (1986). Estradiol can suppress haloperidol-induced supersensitivity in dyskinetic monkeys.Neurosci. Lett. 64206–210.PubMedGoogle Scholar
  7. Calon, F., Goulet, M., Blanchet, P., Martel, J.-C., Bédard, P. J., and Di Paolo, T. (1994). GABAA receptor supersensitivity in the internal segment of the globus pallidus following chronic treatment with a D2 agonist (U-91356A) or Levodopa of MPTP-treated monkeys.17th Annual Meeting of the CCNP, Quebec City, Quebec, Canada, p. 15.Google Scholar
  8. Canonaco, M., Valenti, A., Bettini, E., and Maggi, A. (1989). Differential modulation of [3H]flunitrazepam binding in female rat brain by sex steroid hormones.Eur. J. Pharmacol. 17095–99.PubMedGoogle Scholar
  9. Canonaco, M., Carelli, A., and Maggi, A. (1993). Steroid hormones and receptors of the GABAA supramolecular complex. I. Benzodiazepine receptor level changes in some extrahypothalamic brain areas of the female rat following sex steroid treatment.Neuroendocrinology 57965–973.PubMedGoogle Scholar
  10. Childers, S. E., and Harding, C. M. (1990). Gender, premorbid social functioning and long-term outcome in DMS-III schizophrenia.Schiz. Bull. 16309–318.Google Scholar
  11. Crane, G. E., and Naranjo, E. R. (1971). Motor disorders induced by neuroleptics: A proposed new classification.Arch. Gen. Psychiatry 24179–184.PubMedGoogle Scholar
  12. Crossman, A. R. (1990). A hypothesis on the pathological mechanism that underlie levodopa- or dopamine agonist-induced dyskinesia in Parkinson's disease: Implications for future strategies in treatment.Movement Dis. 5100–108.PubMedGoogle Scholar
  13. Davis, K. L., Kahn, R. S., Ko, G., and Davidson, M. (1991). Dopamine in schizophrenia: A review and reconceptualization.Am. J. Psychiatry 1481474–1486.PubMedGoogle Scholar
  14. Deister, A., and Marneros, A. (1993). Sex-dependent differences in endogenous psychosis. A comparison between schizophrenic, schizo-affective and affective psychoses.Fortsch. Neurol. Psychiatrie 60407–419.Google Scholar
  15. DeLong, M. R. (1990). Primate models of movement disorder of basal ganglia origin.Trends Neurosci. 13281–285.PubMedGoogle Scholar
  16. Diana, M., and Collu, M. (1990). D1 receptors mediated vacuous chewing in the rat: a model of tardive dyskinesia.Pharmacol. Res. 2245.Google Scholar
  17. Di Paolo, T. (1994). Modulation of brain dopamine transmission by sex steroids.Rev. Neurosci. 527–41.PubMedGoogle Scholar
  18. Di Paolo, T., Poyet, P., and Labrie, F. (1982). Effect of prolactin and estradiol on rat striatal dopamine receptors.Life Sci. 312921–2929.PubMedGoogle Scholar
  19. Dworkin, R. H. (1990). Patterns of sex differences in negative symptoms and social functioning consistent with separate dimensions of schizophrenic psychopathology.Am. J. Psychiatry 147347–349.PubMedGoogle Scholar
  20. Farde, L., Wiesel, F. A., Nordstrom, A. L., and Sedvall, G. (1989). D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics.Psychopharmacology 99S28-S31.PubMedGoogle Scholar
  21. Fibiger, H. C., and Lloyd, K. G. (1984). Neurobiological substrates of tardive dyskinesia: The GABA hypothesis.Trends Neurosci. 7462–464.Google Scholar
  22. Fields, J. Z., Wichlinski, L. J., Ritzmann, R. F., Drucker, G. E., and Gordon, J. H. (1991). Cyclo(leu-glu) reverses the permanent dopamine receptor up-regulation induced by ovariectomy.Drug Dev. Res. 23261–268.Google Scholar
  23. Flor-Henry, P. (1985). Schizophrenia: Sex differences.Can. J. Psychiatry 30319–322.PubMedGoogle Scholar
  24. Gerfen, C. R. (1992). The neostriatal mosaic: Multiple levels of compartmental organization in the basal ganglia.Annu. Rev. Neurosci. 15285–320.PubMedGoogle Scholar
  25. Gerfen, C. R., Engber, T. M., Mahan, L. C., Susel, Z., Chase, T. N., Monsma, F. J., and Sibley, D. R. (1990). D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons.Science 2501429–1432.PubMedGoogle Scholar
  26. Gerlach, J. (1988). Tardive dyskinesia. Pathophysiological mechanisms and clinical trials.L'Encéphale XIV227–232.Google Scholar
  27. Goldstein, J. M., and Tsuang, M. T. (1990). Gender and schizophrenia: An introduction and synthesis of findings.Schizo. Bull. 16179–183.Google Scholar
  28. Goldstein, J. M., Santangelo, S. L., Simpson, J. C., and Tsuang, M. T. (1990). The role of gender in identifying subtypes of schizophrenia: A latent class analytic approach.Schizo. Bull. 16263–276.Google Scholar
  29. Gomez-Mancilla, B., Boucher, R., Gagnon, C., Di Paolo, T., Markstein, R., and Bédard, P. J. (1993). Effect of adding the D-1 agonist CY 208-243 to chronic bromocriptine treatment I. Evaluation of motor parameters in relation to striatal catecholamine content and dopamine receptors.Move. Disord. 8144–150.Google Scholar
  30. Gordon, J. H., and Fields, J. Z. (1989). A permanent dopamine receptor up-regulation in the ovariectomized rat.Pharmacol. Biochem. Behav. 33123–125.PubMedGoogle Scholar
  31. Gureje, O. (1991). Gender and schizophrenia: Age at onset and sociodemographic attributes.Acta Psychiatr. Scand. 83402–405.PubMedGoogle Scholar
  32. Häfner, H., Riecher, A., Maurer, K., Löffler, W., Munk-Jorgensen, P., and Strömgren, E. (1989). How does gender influence age at first hospitalization for schizophrenia? A transnational case register study.Psychol. Med. 19903–908.PubMedGoogle Scholar
  33. Häfner, H., Behrens, S., De Vries, D. J., and Gattaz, W. F. (1991). Oestradiol enhances the vulnerability threshold for schizophrenia in women by an early effect on dopaminergic transmission.Eur. Arch. Psychiatry Clin. Neurosci. 24165–68.PubMedGoogle Scholar
  34. Hambrecht, M., Maurer, K., and Häfner, H. (1992). Evidence for a gender bias in epidemiological studies of schizophrenia.Schizo. Res. 8223–231.Google Scholar
  35. Harrison, M. B., Wiley, R. G., and Wooten, G. F. (1990). Selective localization of striatal D1 receptors to striatonigral neurons.Brain Res. 528317–322.PubMedGoogle Scholar
  36. Iacono, W. G., and Beiser, M. (1992). Where are the women in first-episode studies of schizophrenia?Schizo. Bull. 18471–480.Google Scholar
  37. Jüptner, M., Jussofie, A., and Hiembre, C. (1991). Effects of ovariectomy and steroid replacement on GABAA receptor binding in female rat brain.J. Steroid Biochem. Mol. Biol. 38141–147.PubMedGoogle Scholar
  38. Lévesque, D., and Di Paolo, T. (1990). Effect of the rat estrous cycle at ovariectomy on striatal D1 dopamine receptors.Brain Res. Bull. 24281–284.PubMedGoogle Scholar
  39. Lévesque, D., Gagnon, S., and Di Paolo, T. (1989). Striatal D-1 dopamine receptor density fluctuates during the rat estrous cycle.Neurosci. Lett. 98345–350.PubMedGoogle Scholar
  40. Lewine, R. (1985). Schizophrenia: An amotivational syndrome in men.Can. J. Psychiatry 30316–318.PubMedGoogle Scholar
  41. Loranger, A. W. (1984). Sex difference in age at onset of schizophrenia.Arch. Gen. Psychiatry 41157–161.PubMedGoogle Scholar
  42. Lowry, O. H., Rosenbrough, N. J., Farr, A. L., and Randall, R. J. (1951). Protein measurement with folin reagent.J. Biol. Chem. 193265–272.PubMedGoogle Scholar
  43. Marin, C., Parashos, S. A., Kapitzoglou-Logothetis, V., Peppe, A., and Chase, T. N. (1993). D1 and D2 dopamine receptor-mediated mechanisms and behavioral supersensitivity.Pharmacol. Biochem. Behav. 45195–200.PubMedGoogle Scholar
  44. McCabe, M. S. (1975). Demographic difference in functional psychoses.Br. J. Psychiatry 127320–323.PubMedGoogle Scholar
  45. Nicole, L., Lesage, A., and Lalonde, P. (1992). Lower incidence and increased male: female ratio in schizophrenia.Br. J. Psychiatry 161556–557.PubMedGoogle Scholar
  46. Nordstrom, A. L., Farde, L., Wiesel, F. A., Forslund, K., Pauli, S., Halldin, C., and Uppfeldt, G. (1993). Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: A double-blind PET study of schizophrenic patients.Biol. Psychiatr. 33227–235.Google Scholar
  47. O'Connor, L. H., Nork, B., and McEwen, B. S. (1988). Regional specificity of gamma-aminobutyric acid receptor regulation by estradiol.Neuroendocrinology 47473–481.PubMedGoogle Scholar
  48. Opjordsmoen, S. (1991). Long-term clinical outcome of schizophrenia with special reference to gender references.Acta Psychiat. Scand. 83307–313.PubMedGoogle Scholar
  49. Penney, M., and Young, P. (1986). Striatal inhomogeneities and basal ganglia function.Move. Dis. 113–16.Google Scholar
  50. Pogue-Giele, M. F., and Zubin, J. (1988). Negative symptomatology and schizophrenia: A conceptual and empirical review.Int. J. Ment. Health 163–45.Google Scholar
  51. Ring, N., Tantam, D., Montague, L., Newby, D., Black, D., and Morris, J. (1991). Gender differences in the incidence of definite schizophrenia and atypical psychosis—focus on negative symptoms of schizophrenia.Acta Psychiat. Scand. 84489–496.PubMedGoogle Scholar
  52. Rosengarten, H., Schweitzer, J. W., and Friedhoff, A. J. (1983). Induction of oral dyskinesias in naive rats by D1 stimulation.Life sci. 332479–2482.PubMedGoogle Scholar
  53. Seeman, M. V. (1982). Gender differences in schizophrenia.Can. J. Psychiatry 27107–112.PubMedGoogle Scholar
  54. Seeman, M. V. (1985). Sex and schizophrenia.Can. J. Psychiatry 30313–315.PubMedGoogle Scholar
  55. Shirakawa, O., Maeda, K., and Sakai, K. (1993). Dysregulation of striato-nigral GABAergic pathway by chronic haloperidol treatment: The role of dopamine D1 receptor in the substantia nigra reticulata on the development of tardive dyskinesia.Jap. J. Psychiatry Neurol. 47429–430.Google Scholar
  56. Surmeier, D. J., Reiner, A., Levine, M. S., and Ariano, M. A. (1993). Are neostriatal dopamine receptors co-localized?Trends Neurosci. 16299–305.PubMedGoogle Scholar
  57. Yassa, R., and Jeste, D. V. (1992). Gender differences in tardive dyskinesia: A critical review of the literature.Schizo. Bull. 18701–715.Google Scholar

Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Roger Bossé
    • 1
  • Thérèse Di Paolo
    • 1
    • 2
  1. 1.School of PharmacyLaval UniversityQuébecCanada
  2. 2.Department of Molecular Endocrinology, CHUL Research CenterLaval University Medical CenterSte-FoyCanada

Personalised recommendations