RAPID DOWN-REGULATION OF GABA(A) RECEPTORS IN THE GERBIL HIPPOCAMPUS FOLLOWING TRANSIENT CEREBRAL-ISCHEMIA

During transient cerebral ischemia, there is a temporary and robust ac cumulation of extracellular GABA in the hippocampus. We examined wheth er the acute exposure of GABA(A)/benzodiazepine receptors to high conc entrations of GABA early after ischemia results in receptor down-regul ation as observed in vitro. Gerbils were killed 30 and 60 min followin g a 5-min bilateral carotid occlusion, and their brains were prepared for receptor autoradiography. The hydrophilic GABA(A) receptor antagon ist [H-3] SR-95531 and the hydrophobic benzodiazepine agonist [H-3] fl unitrazepam were used to distinguish between cell surface and internal ized receptors. Ischemia significantly decreased [H-3] SR-95531 bindin g in hippocampal areas CAI and CA3 and in the dentate gyrus 30 min aft er ischemia. Scatchard analysis in area CA1 revealed that ischemia dec reased the B-max as low as 44%. The affinity of the remaining sites wa s increased substantially (72% decrease in K-D). As expected, there we re no changes in the binding of [H-3] flunitrazepam to hippocampus in the early postischemic period because the benzodiazepine could bind to both internalized receptors and those on the cell surface. We hypothe size that prolonged exposure (similar to 30-45 min) of GABA(A) recepto rs to high concentrations of synaptic GABA in vivo causes receptor dow n-regulation, perhaps via receptor internalization.