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. 1989 Feb;96(2):409–417. doi: 10.1111/j.1476-5381.1989.tb11832.x

Modulation of the GABAA receptor complex by steroids in slices of rat cuneate nucleus.

J P Turner 1, M A Simmonds 1
PMCID: PMC1854367  PMID: 2538192

Abstract

1. Several derivatives of pregnane and androstane that have hypnotic properties have been investigated for their ability to potentiate responses to the GABAA receptor agonist muscimol and to reduce the effect of the non-competitive GABAA antagonist picrotoxin. 2. Depolarizing responses to muscimol in slices of rat cuneate nucleus were potentiated most potently by 3 alpha-hydroxy,5 alpha-pregnane-11,20-dione (alphaxalone), which gave half-maximal potentiation at 0.15 microM. The 5 beta isomer of alphaxalone had little effect up to 3 microM but in analogues lacking an 11-keto substituent (pregnanolones), both the 5 alpha- and 5 beta-isomers potentiated with potencies 20 and 10 times lower, respectively, than that of alphaxalone. The alpha configuration of the 3-hydroxy was essential in alphaxalone, the 3 beta-hydroxy isomer being inactive. However, there was little difference between the potencies of the 3 alpha- and 3 beta-hydroxy configurations in the pregnanolones, although the maximal effects of the 3 beta-hydroxy isomers were rather lower than those of the 3 alpha-hydroxy isomers. 3. Reductions in the effect of picrotoxin as an antagonist of muscimol were caused most potently by the 3 alpha-hydroxy pregnanolones, with a ten fold reduction in picrotoxin potency at 1 microM concentrations of these steroids. Alphaxalone and its 5 beta-isomer were about half as potent. Androsterone was about 10 times less potent and the 3 beta-hydroxy pregnanolones were ineffective. 4. This difference in the structure-activity relationships for steroidal potentiation of muscimol and reduction in picrotoxin antagonism of muscimol is reminiscent of an analogous distinction found with the barbiturates.

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Selected References

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  1. Atkinson R. M., Davis B., Pratt M. A., Sharpe H. M., Tomich E. G. Action of some steroids on the centtral nervous system of the mouse. II. Pharmacology. J Med Chem. 1965 Jul;8(4):426–432. doi: 10.1021/jm00328a004. [DOI] [PubMed] [Google Scholar]
  2. Barker J. L., Harrison N. L., Lange G. D., Owen D. G. Potentiation of gamma-aminobutyric-acid-activated chloride conductance by a steroid anaesthetic in cultured rat spinal neurones. J Physiol. 1987 May;386:485–501. doi: 10.1113/jphysiol.1987.sp016547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Callachan H., Cottrell G. A., Hather N. Y., Lambert J. J., Nooney J. M., Peters J. A. Modulation of the GABAA receptor by progesterone metabolites. Proc R Soc Lond B Biol Sci. 1987 Aug 21;231(1264):359–369. doi: 10.1098/rspb.1987.0049. [DOI] [PubMed] [Google Scholar]
  4. Cottrell G. A., Lambert J. J., Peters J. A. Modulation of GABAA receptor activity by alphaxalone. Br J Pharmacol. 1987 Mar;90(3):491–500. doi: 10.1111/j.1476-5381.1987.tb11198.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Harrison N. L., Majewska M. D., Harrington J. W., Barker J. L. Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex. J Pharmacol Exp Ther. 1987 Apr;241(1):346–353. [PubMed] [Google Scholar]
  6. Harrison N. L., Simmonds M. A. Modulation of the GABA receptor complex by a steroid anaesthetic. Brain Res. 1984 Dec 10;323(2):287–292. doi: 10.1016/0006-8993(84)90299-3. [DOI] [PubMed] [Google Scholar]
  7. Harrison N. L., Simmonds M. A. Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro. Br J Pharmacol. 1983 Oct;80(2):387–394. doi: 10.1111/j.1476-5381.1983.tb10045.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Holzbauer M. Physiological aspects of steroids with anaesthetic properties. Med Biol. 1976 Aug;54(4):227–242. [PubMed] [Google Scholar]
  9. 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. 1986 May 23;232(4753):1004–1007. doi: 10.1126/science.2422758. [DOI] [PubMed] [Google Scholar]
  10. Mathers D. A., Barker J. L. (-)Pentobarbital opens ion channels of long duration in cultured mouse spinal neurons. Science. 1980 Jul 25;209(4455):507–509. doi: 10.1126/science.6248961. [DOI] [PubMed] [Google Scholar]
  11. Mathers D. A. Pentobarbital promotes bursts of gamma-aminobutyric acid-activated single channel currents in cultured mouse central neurons. Neurosci Lett. 1985 Sep 30;60(2):121–126. doi: 10.1016/0304-3940(85)90231-9. [DOI] [PubMed] [Google Scholar]
  12. Simmonds M. A. Evidence that bicuculline and picrotoxin act at separate sites to antagonize gamma-aminobutyric acid in rat cuneate nucleus. Neuropharmacology. 1980 Jan;19(1):39–45. doi: 10.1016/0028-3908(80)90164-1. [DOI] [PubMed] [Google Scholar]
  13. Simmonds M. A. Presynaptic actions of gamma-aminobutyric acid and some antagonists in a slice preparation of cuneate nucleus. Br J Pharmacol. 1978 Jul;63(3):495–502. doi: 10.1111/j.1476-5381.1978.tb07803.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Simmonds M. A., Turner J. P. Potentiators of responses to activation of gamma-aminobutyric acid (GABAA) receptors. Neuropharmacology. 1987 Jul;26(7B):923–930. doi: 10.1016/0028-3908(87)90071-2. [DOI] [PubMed] [Google Scholar]

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