Chlormethiazole: neurochemical actions at the gamma-aminobutyric acid receptor complex.

Chlormethiazole has been extensively employed as a sedative/hypnotic and anticonvulsant for more than 25 years. While pharmacological and electrophysiological studies have implicated the GABAA receptor complex in these actions, neurochemical findings have not been consistent with this conclusion. We now present evidence that pharmacologically relevant concentrations of chlormethiazole perturb the GABAA receptor complex. Chlormethiazole was found to increase 36Cl- uptake into rat cortical synaptoneurosomes in a concentration-dependent (EC50 = 48 +/- 3 microM; Emax = 8.9 +/- 0.8 nmol Cl-/mg protein per 5 s), picrotoxin-sensitive fashion. Chlormethiazole was also found to inhibit the binding of the 'cage' convulsant [35S]t-butylbicyclophosphorothionate to rat cortical membranes (IC50 = 58.6 +/- 0.6 microM) through an increase in the apparent KD of this radioligand. Moreover, at these concentrations chlormethiazole did not affect pentobarbital-enhanced [3H]flunitrazepam binding, but inhibited [3H]flunitrazepam binding with a low potency (IC50 = 1.6 +/- 0.2 mM). These findings provide neurochemical evidence that pharmacologically relevant concentrations of chlormethiazole can perturb the GABAA receptor complex, and suggest that this compound acts at a distinct locus from other sedative/hypnotics such as barbiturates, benzodiazepines and GABAmimetics.