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

Abstract

1Some pharmacological properties of the GABAA receptor complex in the rat cuneate nucleus slice have been assessed from depolarization responses to the y-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: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 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.

Neuroprotective activity of chlormethiazole following transient forebrain ischaemia in the gerbil

“…Several compounds which enhance inhibitory processes in the hippocampus have been shown to have some neuroprotective effect, particularly when treatment is initiated around the time of the ischaemic episode (Kirino et al, 1986;De Leo et al, 1988;Alps et al, 1988;Taft et al, 1989). Chlormethiazole is an anticonvulsant, sedative and hypnotic drug (Ogren, 1986;Green & Murray, 1989), which acts at the y-aminobutyric acid (GABA) receptor both to potentiate the effects of GABA and to modulate channel opening directly (Harrison & Simmonds, 1983;Moody & Author for correspondence. Skolnick, 1989;Cross et al, 1989).…”

Alfaxalone potentiates and mimics GABA‐induced contractile responses in the guinea‐pig isolated ileum

“…Harrison & Simmonds (1983) have already observed this effect with alfaxalone in the cuneate slice. Also they have drawn attention to the dissociation of potentiation of responses to GABA by anaesthetic barbiturates, in the presence and absence of picrotoxinin, and the ability of agents such as chlormethiazole and anticonvulsant barbiturates to reverse the picrotoxinin-induced depression of maximal responses to GABA whilst showing minimal potentiating action (Harrison & Simmonds, 1983). In this regard, alfaxalone resembles anaesthetic barbiturates rather than the latter anticonvulsants.…”

Pressure reversal of alphaxalone/alphadolone and methohexitone in tadpoles: evidence for different molecular sites for general anaesthesia

“…Not all studies show major differences between the agents. For example, both barbiturates and alphaxalone enhanced depolarizing responses to GABA and muscimol in the rat cuneate nucleus slice with little effect on responses to glycine (Harrison & Simmonds, 1983;, which has been interpreted in terms of the interactions with the GABAA-receptor complex . The question that has to be asked about any study on an individual part of the nervous system is whether the particular effects observed are critical for the production of anaesthesia in the whole animal.…”