Rapid Down-Regulation of GABAA Receptors in the Gerbil Hippocampus Following Transient Cerebral Ischemia |
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Authors: | Bruno Alicke Rochelle D Schwartz-Bloom |
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Institution: | Department of Pharmacology, Duke University Medical Center, Durham, North Carolina, U.S.A. |
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Abstract: | Abstract: During transient cerebral ischemia, there is a temporary and robust accumulation of extracellular GABA in the hippocampus. We examined whether the acute exposure of GABAA/benzodiazepine receptors to high concentrations of GABA early after ischemia results in receptor down-regulation as observed in vitro. Gerbils were killed 30 and 60 min following a 5-min bilateral carotid occlusion, and their brains were prepared for receptor autoradiography. The hydrophilic GABAA receptor antagonist 3H]SR-95531 and the hydrophobic benzodiazepine agonist 3H]flunitrazepam were used to distinguish between cell surface and internalized receptors. Ischemia significantly decreased 3H]SR-95531 binding in hippocampal areas CA1 and CA3 and in the dentate gyrus 30 min after ischemia. Scatchard analysis in area CA1 revealed that ischemia decreased the B max as low as 44%. The affinity of the remaining sites was increased substantially (72% decrease in K D). As expected, there were no changes in the binding of 3H]flunitrazepam to hippocampus in the early postischemic period because the benzodiazepine could bind to both internalized receptors and those on the cell surface. We hypothesize that prolonged exposure (~30–45 min) of GABAA receptors to high concentrations of synaptic GABA in vivo causes receptor down-regulation, perhaps via receptor internalization. |
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Keywords: | Cerebral ischemia GABAA receptor Down - regulation Desensitization Hippocampus Benzo - diazepine |
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