Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Progesterone modulation of D5 receptor expression in hypothalamic ANP neurons, the role of estrogen

Abstract

Aberrant responses to dopamine consequent to a reduction of D1-like receptors in critical regions of the brain have been implicated in schizophrenia.1 Whereas estrogen may protect against the onset and incidence of psychosis in the illness, the neurobiological effects of the ovarian steroid remain unclear.2–4 Recently we have shown that estrogen augments the expression of D5 receptors, a member of the D1-like receptor family, in central neurons and enhances the functions of the host cells.5 Employing rat hypothalamic neuron cultures, we report here that another important ovarian steroid, progesterone, also augments dopamine D5 receptor expression in hypothalamic atrial natriuretic factor (ANP) neurons. However, unlike the effect of estrogen, progesterone acts indirectly through potentiating estrogen-mediated changes that include enhancement of D5 receptor expression, immunoreactive (ir)-ANP release and pro-ANP mRNA abundance. We conclude that whilst progesterone has little effect by itself, the steroid works in synergism with estrogen to augment the function of ANP neurons. The possibility that progesterone may further enhance the protective effect of estrogen against the incidence of psychosis in schizophrenia now needs to be considered.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O et al. Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET Nature 1997 385: 634–636

    Article  CAS  Google Scholar 

  2. Hafner H, Behrens S, De Vry J, Gattaz WF . Oestradiol enhances the vulnerability threshold for schizophrenia in women by an early effect on dopaminergic neurotransmission. Evidence from an epidemiological study and from animal experiments Eur Arch Psychiatry Clin Neurosci 1991 241: 65–68

    Article  CAS  Google Scholar 

  3. Hafner H, Maurer K, Loffler W, Fatkenheuer B, an der Heiden W, Riecher Rossler A et al. The epidemiology of early schizophrenia. Influence of age and gender on onset and early course Br J Psychiatry Suppl 1994 29–38

    Article  Google Scholar 

  4. Hafner H, Heiden W, Behrens S, Gattaz W, Hambrecht M, Loffler W et al. Causes and consequences of the gender difference in age at onset of schizophrenia Schizophr Bull 1998 24: 99–113

    Article  CAS  Google Scholar 

  5. Lee D, Dong P, Copolov DL, Lim AT . D5 dopamine receptors mediate estrogen-induced stimulation of hypothalamic ANP neurons Mol Endocrinol 1999 13: 344–352

    Article  CAS  Google Scholar 

  6. Kulkarni J, Castella A, Smith D, Taffe J, Keks N, Copolov DL . A clinical trial of the effects of estrogen in acutely psychotic women Schizophrenia Res 1996 20: 247–252

    Article  CAS  Google Scholar 

  7. Sanyal S, Van Tol HH . Review the role of dopamine D4 receptors in schizophrenia and antipsychotic action J Psychiatr Res 1997 31: 219–232

    Article  CAS  Google Scholar 

  8. Weinberger DR . The biological basis of schizophrenia: new directions J Clin Psychiatry 1997 58: Suppl 10: 22–27

    Google Scholar 

  9. Brunello N, Masotto C, Steardo L, Markstein R, Racagni G . New insights into the biology of schizophrenia through the mechanism of action of clozapine Neuropsychopharmacology 1995 13: 177–213

    Article  CAS  Google Scholar 

  10. Seeman P, Van Tol HH . Dopamine receptor pharmacology Trends Pharmacol Sci 1994 15: 264–270

    Article  CAS  Google Scholar 

  11. Sanfilipo M, Wolkin A, Angrist B, van Kammen DP, Duncan E, Wieland S et al. Amphetamine and negative symptoms of schizophrenia Psychopharmacol Berl 1996 123: 211–214

    Article  CAS  Google Scholar 

  12. Tiberi M, Caron MG . High agonist-independent activity is a distinguishing feature of the dopamine D1B receptor subtype J Biol Chem 1994 269: 27925–27931

    CAS  PubMed  Google Scholar 

  13. Fink G . Oestrogen and progesterone interactions in the control of gonadotrophin and prolactin secretion J Steroid Biochem 1988 30: 169–178

    Article  CAS  Google Scholar 

  14. Mani SK, Allen JM, Clark JH, Blaustein JD, O'Malley BW . Convergent pathways for steroid hormone- and neurotransmitter-induced rat sexual behavior [published erratum appears in Science 1995; 268: 1833] Science 1994 265: 1246–1249

    Article  CAS  Google Scholar 

  15. Lee D, Huang W, Yang Z, Copolov DL, Lim AT . In vitro evidence for modulation of morphological and functional development of hypothalamic ir-ANP neurons by 3′5′-cyclic-adenosine monophosphate Endocrinology 1992 131: 911–918

    CAS  PubMed  Google Scholar 

  16. Lee D, Huang W, Lim AT . Dopamine induces a biphasic modulation of hypothalamic ANF neurons: a ligand concentration-dependent effect involving D5 and D2 receptor interaction Mol Psychiatry 2000 5: 39–48

    Article  CAS  Google Scholar 

  17. Lee D, Huang W, Copolov DL, Lim AT . Glucocorticoids inhibit D1b, but not D2, receptor-mediated effects on hypothalamic atrial natriuretic factor neurons Endocrinology 1995 136: 5570–5576

    Article  CAS  Google Scholar 

  18. El-Hefnawy T, Manna PR, Luconi M, Baldi E, Slotte JP, Huhtaniemi I . Progesterone action in a murine Leydig tumor cell line (mLTC-1), possibly through a nonclassical receptor type Endocrinology 2000 141: 247–255

    Article  CAS  Google Scholar 

  19. Andreasen EE, Andersen HJ, Jensen HK . Progesterone and gestagen treatment. Pharmacologic and clinical aspects Ugeskr Laeger 1989 151: 2021–2026

    CAS  PubMed  Google Scholar 

  20. de Bold AJ . Atrial natriuretic factor: an overview Fed Proc 1986 45: 2081–2085

    CAS  PubMed  Google Scholar 

  21. Verghese C, de Leon J, Josiassen RC . Problems and progress in the diagnosis and treatment of polydipsia and hyponatremia Schizophr Bull 1996 22: 455–464

    Article  CAS  Google Scholar 

  22. Fuller MA, Jurjus G, Kwon K, Konicki PE, Jaskiw GE . Clozapine reduces water-drinking behavior in schizophrenic patients with polydipsia J Clin Psychopharmacol 1996 16: 329–332

    Article  CAS  Google Scholar 

  23. Carr DB, O'Donnell P, Card JP, Sesack SR . Dopamine terminals in the rat prefrontal cortex synapse on pyramidal cells that project to the nucleus accumbens J Neurosci 1999 19: 11049–11060

    Article  CAS  Google Scholar 

  24. Huang W, Choi CL, Yang Z, Copolov DL, Lim AT . Forskolin induced immunoreactive atrial natriuretic peptide secretion and pro-ANP mRNA expression of hypothalamic neurons in culture: modulation by glucocorticoids Endocrinology 1991 128: 2591–2600

    Article  CAS  Google Scholar 

  25. Huang W, Lee D, Yang Z, Copolov DL, Lim AT . Norepinephrine stimulates immunoreactive (ir) atrial natriuretic peptide (ANP) secretion and pro-ANP mRNA expression from rat hypothalamic neurons in culture: effect of α2-adrenoceptors Endocrinology 1992 130: 2426–2428

    CAS  PubMed  Google Scholar 

  26. Lee D, Huang W, Lim AT . D1 receptors mediate dopamine stimulation of irANF release and pro-ANF mRNA expression of rat hypothalamic neurons in culture Endocrinology 1995 136: 591–597

    Article  CAS  Google Scholar 

  27. Bush AI, Huang W, Copolov DL, Lim AT . Hypothalamic atrial natriuretic peptide secretion plasticity: differential modulation of α- and β-adrenoceptors Neuroendocrinology 1990 52: 65–69

    Article  CAS  Google Scholar 

  28. Lim AT, Dean B, Copolov DL . Evidence for post-translational processing of auriculin B to atriopeptin III immediately prior to secretion by hypothalamic neurons in culture Endocrinology 1990 127: 2598–2600

    Article  CAS  Google Scholar 

  29. Huang W, Lee D, Yang Z, Copolov DL, Lim AT . Plasticity of adrenoceptor responsiveness on irANP secretion and pro-ANP mRNA expression in hypothalamic neuron cultures: modulation by dexamethasone Endocrinology 1992 131: 1562–1564

    Article  CAS  Google Scholar 

  30. Huang W, Lee D, Yang Z, Casley DJ, Throsby M, Copolov DL et al. Evidence for ANP(5–28) production by rat placental cytotrophoblasts Endocrinology 1992 131: 919–924

    CAS  PubMed  Google Scholar 

  31. Throsby M, Lee D, Huang W, Yang Z, Copolov DL, Lim AT . Evidence for ANP(5–28) production by macrophages of the rat spleen: an immunochemical and non-radioactive in situ hybridization approach Endocrinology 1991 129: 991–1000

    Article  CAS  Google Scholar 

  32. Throsby M, Yang Z, Lee D, Huang W, Copolov DL, Lim AT . Co-expression of atrial natriuretic factor and β-endorphin in a sub-population of rat splenic macrophages: age related differences Endocrinology 1993 133: 2889–2896

    Article  CAS  Google Scholar 

  33. Tso JY, Sun XH, Kao TH, Reece KS, Wu R . Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene Nucleic Acids Res 1985 13: 2485–2502

    Article  CAS  Google Scholar 

  34. Piechaczyk M, Blanchard JM, Marty L, Dani C, Panabieres F, El Sabouty S et al. Post-transcriptional regulation of glyceraldehyde-3-phosphate-dehydrogenase gene expression in rat tissues Nucleic Acids Res 1984 12: 6951–6963

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Helen M Schutt Trust, the Woods Family Research Program, a contracted research grant from the State Health Department of Victoria and an equipment grant from The Rebecca L Cooper Medical Research Foundation Ltd, Sydney, Australia.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A T Lim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, D., Wang, L., Dong, P. et al. Progesterone modulation of D5 receptor expression in hypothalamic ANP neurons, the role of estrogen. Mol Psychiatry 6, 112–117 (2001). https://doi.org/10.1038/sj.mp.4000781

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000781

Keywords

This article is cited by

Search

Quick links