gamma-Aminobutyric acid agonists and antagonists alter chloride flux across brain membranes.

gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, increases membrane chloride conductance. Previously, we reported that GABA increases 36Cl- uptake by membrane vesicles (microsacs) prepared from mouse brain. Employing this technique, we found that the GABAA agonists, muscimol, isoguvacine, 4,5,6,7-tetrahydroisoxazolo(5,4-C)pyridine-3-ol, and 3-amino-1-propane sulfonate, all produced a concentration-dependent increase in 36Cl- influx, but baclofen, a GABAB agonist, failed to alter 36Cl- flux. Inhibition of GABA-dependent 36Cl- influx was produced by the convulsant drugs, bicuculline, picrotoxin, and pentylenetetrazole. Ion specificity was demonstrated by a failure of GABA agonists to stimulate influx of 45Ca2+, 86Rb+, 22Na+, or 35SO4(2). GABA-stimulated uptake of 36Cl- was largest in cortex and cerebellum and smaller in hippocampus and striatum. There was little difference in sensitivity to GABA among the areas. Analysis of subcellular fractions prepared from mouse brain demonstrated that the GABA-dependent 36Cl- influx was enriched in the synaptosomal fraction. The nonspecific (GABA-independent) uptake of 36Cl- was enriched in the myelin fraction. These experiments provide evidence for a functional coupling among GABA receptors and the chloride ionophore and suggest that the GABA-activated chloride channel is a site of action for several convulsant compounds.

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