Advertisement

Regulation of Neurosteroid Biosynthesis by Neurotransmitters and Neuropeptides

  • H. Vaudry
  • J.L. Do Rego
  • D. Beaujean-Burel
  • J. Leprince
  • L. Galas
  • D. Larhammar
  • R. Fredriksson
  • V. Luu-The
  • G. Pelletier
  • M.C. Tonon
  • C. Delarue
Part of the Research and Perspectives in Endocrine Interactions book series (RPEI)

Summary

It is now established that the brain has the capability of synthesizing biologically active steroids, termed neurosteroids, that participate in the regulation of various neurophysiological and behavioral processes. However, the neuronal mechanisms regulating the activity of neurosteroid-producing cells have not yet been elucidated. We recently found that, in the frog brain, three enzymes involved in steroid biosynthesis are actively expressed in hypothalamic neurons: 3β-hydroxysteroid dehydrogenase/△5-△4 isomerase (3β-HSD), cytochrome P450 17α-hydroxylase/C17,20-lyase (P450C17) and hydroxysteroid sulfotransferase (HST). Concurrently, we showed that frog hypothalamic explants can convert tritiated pregnenolone ([3H]△5P) into various bioactive steroids, including 17- hydroxypregnenolone (17OH-△5P), progesterone (P), 17-hydroxyprogesterone (17OH-P), dehydroepiandrosterone (DHEA), △5P sulfate (△5PS) and DHEA sulfate (DHEAS). The hypothalamic nuclei, where the 3β-HSD-, P450C17- and HST-expressing neurons are located, receive afferent fibers containing a variety of neurotransmitters and neuropeptides. Here, we show that GABA, endozepines and neuropeptide Y (NPY) regulate neurosteroid biosynthesis.

Double immunohistochemical labeling of hypothalamic slices with antisera against 3β-HSD and various subunits of the GABAA receptor revealed that most 3β-HSD -positive neurons also express the α3 and β2/β3 subunits of the GABAA receptor. Incubation of hypothalamic explants with graded concentrations of GABA induced a dose-dependent inhibition of the conversion of [3H]△5P into radioactive metabolites. The effect of GABA on neurosteroid biosynthesis was mimicked by the GABAA receptor agonist muscimol and was blocked by the selective GABAA receptor antagonists bicuculline and SR95531. The GABAA receptor complex encompasses a central-type benzodiazepine receptor (CBR). Thus, we investigated the effect of the endozepine octadecaneuropeptide (ODN), an endogenous ligand of CBR, on neurosteroid biosynthesis. Using an antiserum against human ODN, we observed that ODN-positive glial cells send thick processes in the close vicinity of 3β-HSD-containing neurons. Incubation of hypothalamic explants with synthetic ODN induced a dose- dependent stimulation of the conversion of [3H]△5P into various neurosteroids. The β-carbolines β-CCM and DMCM, two inverse agonists of CBR, mimicked the stimulatory effect of ODN on neurosteroid biosynthesis, whereas the CBR antagonist flumazenil significantly reduced the stimulatory responses induced by ODN, β-CCM and DMCM. These data indicate that GABA, acting through GABAA receptors, inhibits 3β-HSD activity and that ODN, acting as an inverse agonist on the GABAA/CBR complex, stimulates neurosteroid biosynthesis.

Labeling of brain sections revealed the existence of NPY-immunoreactive varicosities in close proximity to HST-containing perikarya. In situ hybridization studies showed that Y1 and Y5 receptor mRNAs are expressed in the anterior preoptic area and the dorsal magnocellular nucleus. Pulse-chase experiments with 35S-labeled 3′-phosphoadenosine 5′-phosphosulfate as a sulfate donor, and [3H]△5P or [3H]DHEA as a steroid precursor, demonstrated that NPY inhibits the conversion of △5P into △5PS and DHEA into DHEAS by hypothalamic explants. The inhibitory effect of NPY on the formation of sulfated neurosteroids was mimicked by PYY, a non-selective NPY receptor agonist, and by [Leu31,Pro34]NPY, an agonist for non-Y2 receptors, and was completely suppressed by the Y1 receptor antagonist BIBP3226. Conversely, the Y2 receptor agonist NPY(13–36) and the Y5 receptor agonist [D-Trp32]NPY did not affect the biosynthesis of △5PS and DHEAS. These data indicate that NPY, acting through Y1 receptors, exerts an inhibitory influence on the biosynthesis of sulfated neurosteroids. The present study provides evidence that, in the brain, neurostransmitters and neuropeptides regulate the activity of neurosteroid- producing neurons. Since neurosteroids have been implicated in the control of a number of behavioral and metabolic activities, these data strongly suggest that some of the neurophysiological effects of neurotransmitters and neuropeptides can be mediated through modulation of neurosteroid biosynthesis.

Keywords

GABAA Receptor Inverse Agonist Neuroactive Steroid Pregnenolone Sulfate Diazepam Binding Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Beaujean D, Mensah-Nyagan AG, Do Rego JL, Luu-The V, Pelletier G, Vaudry H (1999) Immunocytochemical localization and biological activity of hydroxysteroid sulfotransferase in the frog brain. J Neurochem 72: 848–857CrossRefPubMedGoogle Scholar
  2. Beaujean D, Do Rego JL, Galas L, Mensah-Nyagan AG, Fredriksson R, Larhammar D, Fournier A, Luu-The V, Pelletier G, Vaudry H (2002) Neuropeptide Y inhibits the biosynthesis of sulfated neurosteroids in the hypothalamus through activation of Y1 receptors. Endocrinology 143: 1950–1963CrossRefPubMedGoogle Scholar
  3. Cailliez D, Danger JM, Andersen AC, Polak JM, Pelletier G, Kawamura K, Kikuyama S, Vaudry H (1987) Neuropeptide Y (NPY)-like immunoreactive neurons in the brain and pituitary of the amphibian Rana catesbeiana. Zool Sci 4: 123–134Google Scholar
  4. Chartrel N, Conlon JM, Danger JM, Fournier A, Tonon MC, Vaudry H (1991) Characterization of melanotropin release-inhibiting factor (melanostatin) from frog brain: homology with human neuropeptide Y. Proc Natl Acad Sci USA 88: 3862–33866PubMedGoogle Scholar
  5. Corpéchot C, Robel P, Axelsön M, Sjövall J, Baulieu EE (1981) Characterization and measurement of dehydroepiandrosterone sulfate in the rat brain. Proc Natl Acad Sci USA 78:4704–4707PubMedGoogle Scholar
  6. Corpéchot C, Synguelakis M, Talha S, Axelson M, Sjovall J, Vihko R, Baulieu EE, Robel P (1983) Pregnenolone and its sulfate ester in the rat brain. Brain Res 270:119–125CrossRefPubMedGoogle Scholar
  7. Covey DF, Evers AS, Mennerick S, Zorumski CF, Purdy RH (2001) Recent development in structure-activity relationships for steroid modulators of GABAA receptors. Brain Res Rev 37:91–97CrossRefPubMedGoogle Scholar
  8. Danger JM, Guy J, Benyamina M, Jégou S, Leboulenger F, Coté J, Tonon MC, Pelletier G, Vaudry H (1985) Localization and identification of neuropeptide Y (NPY)-like immunoreactivity in the frog brain. Peptides 6: 1225–1236CrossRefPubMedGoogle Scholar
  9. Do Rego JL, Mensah-Nyagan AG, Feuilloley M, Ferrara P, Pelletier G, Vaudry H (1998) The endozepine triakontatetraneuropeptide diazepam-binding inhibitor [17–50] stimulates neurosteroid biosynthesis in the frog hypothalamus. Neuroscience 83: 555–570CrossRefPubMedGoogle Scholar
  10. Do Rego JL, Mensah-Nyagan AG, Beaujean D, Vaudry D, Sieghart W, Luu-The V, Pelletier G, Vaudry H (2000) γ-Aminobutyric acid, acting through γ-aminobutyric acid type A receptors, inhibits the biosynthesis of neurosteroids in the frog hypothalamus. Proc Natl Acad Sci USA 97: 13925–13930CrossRefPubMedGoogle Scholar
  11. Do Rego JL, Mensah-Nyagan AG, Beaujean D, Leprince J, Tonon MC, Luu-The V, Pelletier G, Vaudry H (2001) The octadecaneuropeptide ODN stimulates neurosteroid biosynthesis through activation of central-type benzodiazepine receptors. J Neurochem 76: 128–138CrossRefPubMedGoogle Scholar
  12. Duparc C, Lefebvre H, Tonon MC, Vaudry H, Kuhn JM (2003) Characterization of endozepines in the human testicular tissue: effect of triakontatetraneuropeptide on testosterone secretion. J Clin Endocrinol Metab 88: 5521–5528CrossRefPubMedGoogle Scholar
  13. Ferrero P, Santi MR, Conti-Tronconi B, Costa E, Guidotti A (1986) Study of an octadecaneuropeptide derived from diazepam binding inhibitor (DBI): biological activity and presence in rat brain. Proc Natl Acad Sci USA 83: 827–831PubMedGoogle Scholar
  14. Franzoni MF, Morino P (1989) The distribution of GABA-like-immunoreactive neurons in the brain of the newt, Triturus cristatus carnifex, and the green frog Rana esculenta. Cell Tissue Res 255: 155–166CrossRefPubMedGoogle Scholar
  15. Guidotti A, Forchetti CM, Corda MG, Konkel D, Bennett CD, Costa E (1983) Isolation, characterization, and purification to homogeneity of an endogenous polypeptide with agonistic action on benzodiazepine receptors. Proc Natl Acad Sci USA 80: 3531–3535PubMedGoogle Scholar
  16. Hevers W, Luddens H (1998) The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes. Mol Neurobiol 18: 35–86PubMedGoogle Scholar
  17. Kavaliers M, Kinsella DM (1995) Male preference for the odors of estrous female mice is reduced by the neurosteroid pregnenolone sulfate. Brain Res 682: 222–226CrossRefPubMedGoogle Scholar
  18. Lázár G, Maderdrut JL, Trasti SL, Liposits Z, Toth P, Kovicz T, Merchenthaler I (1993) Distribution of proneuropeptide Y-derivated peptides in the brain of Rana esculenta and Xenopus laevis. J Comp Neurol 327: 551–571CrossRefPubMedGoogle Scholar
  19. Le Goascogne C, Robel P, Gouézou M, Sananès N, Baulieu EE, Waterman M (1987) Neurosteroids: cytochrome P450scc in rat brain. Science 237: 1212–1215PubMedGoogle Scholar
  20. Majewska MD (1992) Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol 38: 379–385CrossRefPubMedGoogle Scholar
  21. McEwen BS (1994) Endocrine effects on the brain and their relationship to behavior. In: Siegel GJ, Agranoff BW, Albers RW, Molinoff B (eds) Basic neurochemistry. Raven Press, New York, pp 1003–1023Google Scholar
  22. Mellon S, Vaudry H (2001) Biosynthesis of neurosteroids and regulation of their synthesis. Int Rev Neurobiol 46: 33–78PubMedGoogle Scholar
  23. Mensah-Nyagan AG, Feuilloley M, Dupont E, Do Rego JL, Leboulenger F, Pelletier G, Vaudry H (1994) Immunocytochemical localization and biological activity of 3β-hydroxysteroid dehydrogenase in the central nervous system of the frog. J Neurosci 14: 7306–7318PubMedGoogle Scholar
  24. Mensah-Nyagan AG, Do-Rego JL, Beaujean D, Luu-The V, Pelletier G, Vaudry H (1999) Neurosteroid: expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system. Pharmacol Rev 51: 63–82PubMedGoogle Scholar
  25. Reddy DS, Kulkarni SK (1998) The role of the GABA-A and mitochondrial diazepam-binding inhibitor receptors on the effects of neurosteroids on food intake in mice. Psychopharmacology 137: 391–400CrossRefPubMedGoogle Scholar
  26. Robel P, Baulieu EE (1994) Neurosteroids. Biosynthesis and function. Trends Endocrinol Metab 5: 1–8CrossRefGoogle Scholar
  27. Robel P, Corpéchot C, Clarke C, Groyer A, Synguelakis M, Vourc’h C, Baulieu EE (1986) Neurosteroids: 3β-hydroxy-△5-derivatives in the rat brain. In: Fink AJ, Harmar AJ, McKerns KW (eds) Neuroendocrine molecular biology. Plenum Press, New York, pp 367–377Google Scholar
  28. Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404: 661–671PubMedGoogle Scholar
  29. Slobodyansky E, Guidotti A, Wambebe C, Berkovich A, Costa E (1989) Isolation and characterization of a rat brain triakontatetraneuropeptide, a posttranslational product of diazepam binding inhibitor: specific action at the Ro5-4864 recognition site. J Neurochem 53: 1276–1284PubMedGoogle Scholar
  30. Wehrenberg WB, Corder R, Gaillard RC (1989) A physiological role for neuropeptide Y in regulating the estrogen/progesterone induced luteinizing hormone surge in ovariectomized rats. Neuroendocrinology 49: 680–682PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • H. Vaudry
    • 1
  • J.L. Do Rego
    • 1
  • D. Beaujean-Burel
    • 1
  • J. Leprince
    • 1
  • L. Galas
    • 1
  • D. Larhammar
    • 2
  • R. Fredriksson
    • 2
  • V. Luu-The
    • 3
  • G. Pelletier
    • 3
  • M.C. Tonon
    • 1
  • C. Delarue
    • 1
  1. 1.European Institute for Peptide Research, Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U413, UA CNRSUniversity of RouenMont- Saint-AignanFrance
  2. 2.Department of Neuroscience, Unit of PharmacologyUppsala UniversityUppsalaSweden
  3. 3.Laboratory of Molecular Endocrinology and OncologyLaval University Medical CenterCanada

Personalised recommendations