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GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid

Nature volume 392, pages 926–929 (1998)Cite this article

Abstract

The hormone progesterone is readily converted to 3α-OH-5α-pregnan-20-one (3α,5α-THP) in the brains of males and females1,2. In the brain, 3α,5α-THP acts like a sedative3,4,5, decreasing anxiety and reducing seizure activity, by enhancing the function of GABA (γ-aminobutyric acid)6,7,8, the brain's major inhibitory neurotransmitter. Symptoms of premenstrual syndrome (PMS), such as anxiety9 and seizure10,11 susceptibility, are associated with sharp declines in circulating levels of progesterone and, consequently, of levels of 3α,5α-THP in the brain. Abrupt discontinuation of use of sedatives such as benzodiazepines12 and ethanol13 can also produce PMS-like withdrawal symptoms. Here we report a progesterone-withdrawal paradigm, designed to mimic PMS and post-partum syndrome in a rat model. In this model, withdrawal of progesterone leads to increased seizure susceptibility and insensitivity to benzodiazepine sedatives through an effect on gene transcription. Specifically, this effect was due to reduced levels of 3α,5α-THP which enhance transcription of the gene encoding the α4 subunit of the GABAA receptor. We also find that increased susceptibility to seizure after progesterone withdrawal is due to a sixfold decrease in the decay time for GABA currents and consequent decreased inhibitory function. Blockade of the α4 gene transcript prevents these withdrawal properties. PMS symptoms may therefore be attributable, in part, to alterations in expression of GABAA receptor subunits as a result of progesterone withdrawal.

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Figure 1: Profile of altered GABAA pharmacology following ‘withdrawal’ of progesterone.
Figure 2: α4 antisensense oligonucleotide prevents the withdrawal properties of progesterone.
Figure 3: Effects of progesterone withdrawal on seizures.
Figure 4: Progesterone withdrawal increases protein and mRNA levels of the GABAA receptor α4 subunit.

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References

  1. Smith, S. S. Female sex steroids: from receptors to networks to performance—actions on the sensorimotor system. Prog. Neurobiol. 44, 55–86 (1994).

    Article  CAS  Google Scholar 

  2. Purdy, R. H., Morrow, A. L., Moore, P. H. J & Paul, S. M. Stress-induced elevations of GABA type A receptor-active steroids in the rat brain. Proc. Natl Acad. Sci. USA 88, 4553–4557 (1991).

    Article  ADS  CAS  Google Scholar 

  3. Bitran, D., Hilvers, R. J. & Kellogg, C. K. Anxiolytic effects of 3α-OH-5α[β]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAAreceptor. Brain Res. 561, 157–161 (1991).

    Article  CAS  Google Scholar 

  4. Brot, M. D., Akwa, Y., Purdy, R. H., Koob, G. F. & Britton, K. T. The anxiolytic-like effects of the neurosteroid allopregnanolone–interactions with GABAAreceptors. Eur. J. Pharmacol. 325, 1–7 (1997).

    Article  CAS  Google Scholar 

  5. Belelli, D., Bolger, M. B. & Gee, K. Anticonvulsant profile of the progesterone metabolite 5α-pregnan-3α-ol-20-one. Eur. J. Pharmacol. 166, 325–329 (1989).

    Article  CAS  Google Scholar 

  6. Majewska, M. D., Harrison, N. L., Schwartz, R. D., Barker, J. L. & Paul, S. M. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232, 1004–1007 (1986).

    Article  ADS  CAS  Google Scholar 

  7. Smith, S. S., Waterhouse, B. . D., Chapin, J. K. & Woodward, D. J. Progesterone alters GABA and glutamate responsiveness: a possible mechanism for its anxiolytic action. Brain Res. 400, 353–359 (1987).

    Article  CAS  Google Scholar 

  8. Twyman, R. E. & MacDonald, R. L. Neurosteroid regulation of GABAAreceptor-single channel kinetic properties of mouse spinal cord neurons in culture. J. Physiol. (Lond.) 456, 215–245 (1992).

    Article  CAS  Google Scholar 

  9. Dennerstein, L. et al. Progesterone and premenstrual syndrome: a double blind crossover trial. Brit. Med. J. 290, 1617–1621 (1985).

    Article  CAS  Google Scholar 

  10. Backstrom, T., Zetterlund, B., Blom, S. & Romano, M. Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy. Acta Neurol. Scand. 69, 240–248 (1984).

    Article  CAS  Google Scholar 

  11. Herzog, A. G. Progesterone therapy in women with complex partial and secondary generalized seizures. Neurology 45, 1660–1662 (1995).

    Article  CAS  Google Scholar 

  12. File, S. E. The history of benzodiazepine dependence: a review of animal studies. Neurosci. Biobehav. Rev. 14, 135–146 (1990).

    Article  CAS  Google Scholar 

  13. Kokka, N., Sapp, D. W., Taylor, A. M. & Olsen, R. W. The kindling model of alcohol dependence: similar persistent reduction in seizure threshold to pentylenetetrazol in animals receiving chronic ethanol or chronic pentylenetetrazol. Alcohol Clin. Exp. Res. 17, 525–531 (1993).

    Article  CAS  Google Scholar 

  14. Costa, A.-M. N., Spence, K. T., Smith, S. S. & ffrench-Mullen, J. M. H. Withdrawal from the endogenous steroid progesterone results in GABAAcurrents insensitive to benzodiazepine modulation in rat CA1 hippocampus. J. Neurophys. 74, 464–469 (1995).

    Article  CAS  Google Scholar 

  15. Friedman, L., Gibbs, T. T. & Farb, D. H. γ-Aminobutyric acidAreceptor regulation: Chronic treatment with pregnanolone uncouples allosteric interactions between steroid and benzodiazepine recognition sites. Mol. Pharmacol. 44, 191–197 (1993).

    CAS  PubMed  Google Scholar 

  16. Buck, K. J. & Harris, R. A. Benzodiazepine agonist and ivnerse agonist actions on GABAAreceptor-operated chloride channels. II. Chronic effects of ethanol. J. Pharmacol. Exp. Ther. 253, 713–719 (1990).

    CAS  PubMed  Google Scholar 

  17. Yu, X. J. & Ticku, M. K. Chronic neurosteroid treatment produces functional heterologous uncoupling at the gamma-aminobutyric acid type A/benzodiazepine receptor complex in mammalian cortical neurons. Mol. Pharmacol. 47, 603–610 (1994).

    Google Scholar 

  18. Ator, N. A., Grant, K. A., Purdy, R. H., Paul, S. M. & Griffiths, R. R. Drug discrimination analysis of endogenous neuroactive steroids in rats. Eur. J. Pharmacol. 241, 237–243 (1993).

    Article  CAS  Google Scholar 

  19. Sundstrom, I., Ashbrook, D. & Backstrom, T. Reduced benzodiazepine sensitivity in patients with premenstrual syndrome—a pilot study. Psychoneuroendo 22, 25–38 (1997).

    Article  CAS  Google Scholar 

  20. Gallo, M. A. & Smith, S. S. Progesterone withdrawal decreases latency to and increases duration of electrified prod burial: a possible rat model of PMS anxiety. Pharmacol. Biochem. Behav. 46, 897–904 (1993).

    Article  CAS  Google Scholar 

  21. Wafford, K. A. et al. Functional characterization of human GABA receptors containing the α4 subunit. Mol. Pharmacol. 50, 670–678 (1996).

    CAS  PubMed  Google Scholar 

  22. Wisden, W. et al. Cloning, pharmacological characteristics and expression pattern of the rate GABAAreceptor α4 subunit. FEBS Lett. 289, 227–230 (1991).

    Article  CAS  Google Scholar 

  23. Mahmoudi, M., Kang, M. H., Tillakaratne, N., Tobin, A. J. & Olsen, R. W. Chronic intermittent ethanol treatment in rats increases GABAAreceptor α4 subunit expression–possible relevance to alcohol dependence. J. Neurochem. 68, 2485–2492 (1997).

    Article  CAS  Google Scholar 

  24. Devaud, L. L., Fritschy, J. M., Sieghart, W. & Morrow, A. L. Bidirectional alterations of GABAAreceptor subunit peptide levels in rat cortex during chronic ethanol consumption and withdrawal. J. Neurochem. 69, 126–130 (1997).

    Article  CAS  Google Scholar 

  25. Holt, R. A., Bateson, A. N. & Martin, I. L. Chronic treatment with diazepam or abecarnil differently affects the expression of GABAAreceptor subunit mRNAs in the rat cortex. Neuropharmacol. 35, 1457–1463 (1996).

    Article  CAS  Google Scholar 

  26. Lavoie, A. M., Tingey, J. J., Harrison, N. L., Pritchett, D. B. & Twyman, R. E. Activation and deactivation rates of recombinant GABA(A) receptor channels are dependent on alpha-subunit isoform. Biophys. J. 73, 1–9 (1997).

    Article  Google Scholar 

  27. Kern, W. & Sieghart, W. Polyclonal antibodies directed against an epitope specific for the α4-subunit of GABAAreceptors identify a 67-kDa protein in rat brain membranes. J. Neurochem. 62, 764–769 (1994).

    Article  CAS  Google Scholar 

  28. Mossier, B., Togel, M., Fuchs, K. & Sieghart, W. Immunoaffinity purification of GABAAreceptors containing γ2 subunits. J. Biol. Chem. 269, 25777–25782 (1994).

    CAS  PubMed  Google Scholar 

  29. Tyndale, R. F., Hales, T. G., Olsen, R. W. & Tobin, A. J. Distinctive patterns of GABAAreceptor subunit mRNAs in 13 cell lines. J. Neurosci. 14, 5417–5428 (1994).

    Article  CAS  Google Scholar 

  30. Lau, E. C., Li, Z.-Q., Santos, V. & Slavkin, H. C. Messenger RNA phenotyping for semi-quantitative comparison of glucocorticoid receptor transcript levels in the developing embryonic mouse palate. J. Steroid Biochem. Mol. Biol. 46, 751–758 ((1993).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank I. Fischer for assistance; Hoffman-La Roche for the RO15-1788 sample; D.S. Faber, M. M. McCarthy and D. H. Smith for critical reading of the manuscript; and D. O'Reilly for editorial comments. The work was supported by a grant from the NIH.

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Authors and Affiliations

  1. Department of Neurobiology and Anatomy, Allegheny University of the Health Sciences, EPPI, 3200 Henry Avenue, Philadelphia, 19129, Pennsylvania, USA

    Sheryl S. Smith, Qi Hua Gong, Fu-Chun Hsu, Ronald S. Markowitz & Xinshe Li

  2. RIN Bioscience, Zeneca Pharmaceuticals, Zeneca Inc., Wilmington, 198505437, Delaware, USA

    J. M. H. ffrench-Mullen

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  1. Sheryl S. Smith
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Correspondence to Sheryl S. Smith.

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Smith, S., Gong, Q., Hsu, FC. et al. GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392, 926–929 (1998). https://doi.org/10.1038/31948

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