Distinction Between the Effects of Barbiturates, Benzodiazepines and Phenytoin on Responses to Γ‐aminobutyric Acid Receptor Activation and Antagonism by Bicuculline and Picrotoxin

Abstract

1 Interactions of depressant and anticonvulsant drugs with the neuronal y-aminobutyric acid (GABA) receptor+effector system have been examined on afferent fibres to the rat cuneate nucleus in vitro. Three types of interaction have been measured: (a) potentiation of depolarizing responses to the GABA analogue, muscimol: (b) reduction in the potency of bicuculline as an antagonist of muscimol at the GABA receptor: (c) reduction in the potency of picrotoxin as an antagonist of muscimol acting on the effector mechanism. 2 Phenobarbitone reduced the potency of picrotoxin in doses which did not affect the potency of bicuculline and which caused only a small potentiation of muscimol. Pentobarbitone did not show such selectivity, a reduction in potency of picrotoxin always being accompanied by a reduction in potency of bicuculline and a substantial potentiation of muscimol. 3 Flurazepam and lorazepam both reduced the potency of picrotoxin without affecting that of bicuculline and with very little potentiation of muscimol. Phenytoin had no effect on the potency of picrotoxin whilst potentiating muscimol to the same extent as phenobarbitone. 4 The spectrum of drug activity in reducing the potency of picrotoxin correlates well with the reported anticonvulsant effects of these drugs against kindled amygdaloid seizures. Potentiation of muscimol and reduction of bicuculline potency appear more closely related to hypnotic properties.

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

“…With the exception of 100 gM pentobarbitone which causes a small but consistent depolarization (Simmonds, 1981) A Reversal of bicuculline antagonism of GABA on rat superior cervical ganglion: potency relative to pentobarbitone (Bowery & Dray, 1978). B Enhancement of [3H]-GABA binding to rat brain membranes, relative to the effect of pentobarbitone, at 500 Mm concentrations (Olsen & Snowman, 1982).…”

“…Picrotoxin antagonizes GABA and its analogue muscimol in a manner that is not competitive (Simmonds, 1980), while benzodiazepines potentiate responses to GABA and muscimol (Choi, Farb & Fischbach, 1977;MacDonald & Barker, 1978;Simmonds, 1981). Barbiturates also have a modulatory influence on this complex that results in potentiations of GABA and muscimol (Nicoll, 1975;Ransom & Barker, 1976;Barker & Ransom, 1978;Brown & Constanti, 1978;Schlosser & Franco, 1979;Simmonds, 1981).…”

Comparison of the effects of bicuculline and strychnine on brain stem auditory evoked potentials in the cat

“…This is consistent with the observation that neither diphenylhydantoin nor benzodiazepines affect BAEPs (Stockard, Rossiter, Jones & Sharbrough, 1977). Both are believed to modulate GABA-induced responses (Straughan, 1979;Olsen, 1981;Simmonds, 1981). Penicillin on the other hand is a GABA antagonist and also has no effect on the BAEP (Stockard et al, 1977).…”

Proceedings of the Physiological Society, 14‐15 February 1992, Bristol Meeting: Communications

“…Diazepam and tizanidine have centrally acting muscle relaxant properties. The depressant activity of diazepam has been associated with potentiation of primary afferent depolarization (PAD) in vivo (Polc & Haefely, 1976) and potentiation of the effects of GABA at GABAA receptors (Simmonds, 1981).…”