Adaptive changes in the NMDA receptor complex in rat hippocampus after chronic treatment with CGP 39551.
Academic Article
Overview
abstract
Chronic treatment of adult rats with DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic carboxyethylester (CGP 39551) (30 mg/kg orally for 12 days) induced a significant increase, 72 h after the last dose, in the N-methyl-D-aspartate (NMDA)-sensitive [3H]glutamate binding in the hippocampal pyramidal layer (stratum oriens CA1, CA3: +51% on average; stratum radiatum CA1, CA3: +40% on average; stratum pyramidale CA1: +20%, CA3: +55%) and in the dentate gyrus (+43%) compared to vehicle-injected animals, as assessed by quantitative receptor autoradiography. Similar results were obtained using the NMDA receptor antagonist, [3H]DL-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP 39653). Saturation experiments showed that the increase in [3H]CGP 39653 binding was due to the maximum number of receptors, without changes in affinity. The same regimen did not alter [3H]N-(1-[2-thienyl]-cyclohexyl)-3,4-piperidine (TCP) binding to the ion channel coupled to the receptor but prevented D-serine (5 microM)-induced enhancement of [3H]glutamate binding. NMDA (3-300 microM) enhanced [3H]noradrenaline release from hippocampal slices, and 7-Cl-kynurenic acid (5-100 microM) and (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclo-hepten-5,10-imine maleate (MK 801) (0.03-0.3 microM), antagonists at the glycine site and ion channel respectively, antagonized this effect to the same extent in CGP 39551-treated rats and controls. Chronic CGP 39551 did not affect the neurotoxic potency of quinolinic acid, a selective agonist at the NMDA receptor, injected in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)
