gamma-Hydroxybutyric acid binding sites: evidence for coupling to a chloride anion channel

The effect of eight anions, including chloride, on the binding of gamma-hydroxy2,3-3H]butyric acid (GHB) to synaptosomal membranes of rat and human brain was ascertained, as was the effect of a number of other allosteric modulators of the GABA/benzodiazepine/picrotoxin complex. All ions which were active at the chloride ion channel, inhibited the binding of 3H]GHB in a dose-dependent manner, with maximum inhibition of binding being 60% of 300 mM concentration of anion. Inactive ions in this binding system included sulfate, acetate and fluoride, all impermeable to the chloride ion channel. The inhibition of binding was temperature-dependent, being abolished at 37 degrees C and was independent of the cation used. The binding of 3H]GHB was also enhanced by pentobarbital, picrotoxin and diazepam but unchanged in the presence of GABA, muscimol, bicuculline, baclofen or strychnine. These data raise the possibility that the epileptogenic effect of GHB may be modulated by an action on the chloride ion channel, that is tightly coupled to the GABA/benzodiazepine/picrotoxin and/or GHB receptor complex.