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

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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 3α-hydroxy, 5α-pregnane-11,20-dione (alphaxalone), which gave half-maximal potentiation at 0.15 μm. The 5β isomer of alphaxalone had little effect up to 3 μm but in analogues lacking an 11-keto substituent (pregnanolones), both the 5α- and 5β-isomers potentiated with potencies 20 and 10 times lower, respectively, than that of alphaxalone. The a configuration of the 3-hydroxy was essential in alphaxalone, the 3β-hydroxy isomer being inactive. However, there was little difference between the potencies of the 3α- and 3β-hydroxy configurations in the pregnanolones, although the maximal effects of the 30-hydroxy isomers were rather lower than those of the 3α-hydroxy isomers. 3 Reductions in the effect of picrotoxin as an antagonist of muscimol were caused most potently by the 3α-hydroxy pregnanolones, with a ten fold reduction in picrotoxin potency at 1 μm concentrations of these steroids. Alphaxalone and its 5β-isomer were about half as potent. Androsterone was about 10 times less potent and the 3β-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.