Adaptive changes in the NMDA receptor complex in rat hippocampus after chronic treatment with CGP 39551

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 396653). 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 μM)-induced enhancement of [³H]glutamate binding. NMDA (3-300 μM) enhanced [³H]noradrenaline release from hippocampal slices, and 7-Cl-kynurenic acid (5-100 μM) and (+)-5-methyl-10, 11-dihydro-5H-dibenzo- [a,d]cyclo-hepten-5, 10-imine maleate (MK 801) (0.03-0.3 μM), 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. The sensitivity of the NMDA receptor complex to selective agonists or antagonists, thus, does not appear to be altered by chronic treatment with CGP 39551 in adult rats in spite of an increase in the density of the agonist recognition sites. Therefore tolerance is not likely to develop to the pharmacological actions of the drug, and endogenously released excitatory amino acids should not have deleterious effects due to their interaction with a higher amount of NMDA receptors after withdrawal of CGP 39551.