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

Some pharmacological properties of the GABAA receptor complex in the rat cuneate nucleus slice have been assessed from depolarization responses to the gamma-aminobutyric acid (GABA) analogue muscimol and antagonism of the responses by bicuculline and picrotoxin. 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 greater than (+/-)-methyl-phenobarbitone = (-)-methylphenobarbitone greater than butobarbitone = chlormethiazole greater than phenobarbitone greater than 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. 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. It is suggested that a specific site of action in the GABAA 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.