Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro

Abstract

1 Some pharmacological properties of the GABA_A receptor complex in the rat cuneate nucleus slice have been assessed from depolarization responses to the γ-aminobutyric acid (GABA) analogue muscimol and antagonism of the responses by bicuculline and picrotoxin. 2 Responses to muscimol were potentiated by the following drugs, in descending order of potency with regard to the concentrations required in the Krebs medium: (±)-5-(1,3-dimethylbutyl)-5-ethylbarbituric acid ((±)-DMBB) = (±)-quinalbarbitone = (± pentobarbitone > (±)-methyl-phenobarbitone = (−)-methylphenobarbitone > butobarbitone = chlormethiazole > phenobarbitone > barbitone = (+)-methylphenobarbitone. Primidone and phenylethylmalonamide were inactive. Calculation of the concentrations likely to be present in membrane lipids for equal potentiations of muscimol revealed little difference between quinalbarbitone, pentobarbitone, phenobarbitone and barbitone. 3 The effect of picrotoxin as a muscimol antagonist was selectively reduced only by DMBB, chlormethiazole, phenobarbitone and (−)-methylphenobarbitone in concentrations that caused only a modest potentiation of muscimol. 4 It is suggested that a specific site of action in the GABA_A receptor complex is involved in the reduction of picrotoxin effect and that this may be relevant to the anticonvulsant properties of chlormethiazole, phenobarbitone and (−)-methylphenobarbitone. The potentiation of muscimol by chlormethiazole and the barbiturates in general involves a distinctly different site that is less selective and this may underlie the hypnotic properties of these drugs.