The modulation by chlormethiazole of the GABAA‐receptor complex in rat brain

Abstract

1 The interactions of chlormethiazole with γ-aminobutyric acid (GABA) synthesis and release, and with ligand binding to sites associated with the GABA_A-receptor complex and the GABA_B-receptor have been studied in the rat. The GABA_A-receptor was studied using [³H]-muscimol, [³H]-flunitrazepam was used to label the benzodiazepine modulatory site, and [³⁵S]-butylbicyclophosphorothionate ([³⁵S]-TBPS) to label the chloride channel. 2 Chlormethiazole had no effect on GABA synthesis in the cortex, hippocampus and striatum or on GABA release from cortical slices in vitro. Chlormethiazole did not displace [³H]-baclofen binding to the GABA_B-receptor. 3 Chlormethiazole (IC₅₀ = 140 μm) and pentobarbitone (IC₅₀ = 95 μm) both inhibited [³⁵S]-TBPS binding by increasing the rate of [³⁵S]-TBPS dissociation. In addition, chlormethiazole caused an apparent decrease in the affinity of [³⁵S]-TBPS binding. 4 Chlormethiazole enhanced the binding of [³H]-muscimol but had no effect on [³H]-flunitrazepam binding. In contrast, the sedative barbiturate pentobarbitone enhanced both [³H]-muscimol and [³H]-flunitrazepam binding. 5 It is concluded that the sedative and anticonvulsant effects of chlormethiazole are probably mediated through an action at the GABA_A-receptor. However, chlormethiazole does not interact with the GABA_A-receptor complex in an identical manner to the sedative barbiturate pentobarbitone.