Chlormethiazole: neurochemical actions at the γ-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 GABA A 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 GABA A receptor complex. Chlormethiazole was found to increase 36Cl − uptake into rat cortical synaptoneurosomes in a concentration-dependent (EC 50 = 48 ± 3 μM; E max = 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 (IC 50 = 58.6 ± 0.6 μM) through an increase in the apparent K D of this radioligand. Moreover, at these concentrations chloromethiazole did not affect pentobarbital-enhanced [ 3H]flunitrazepam binding, but inhibited [ 3H]flunitrazepam binding with a low potency (IC 50 = 1.6 ± 0.2 mM). These findings provide neurochemical evidence that pharmacologically relevant concentrations of chlormethiazole can perturb the GABA A receptor complex, and suggest that this compound acts at a distinct locus from other sedative/hypnotics such as barbiturates, benzodiazepines and GABAmimetics.