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 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)
Mennini
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Istituto di Richerche Farmacologiche Mario Negri, Milano, Italy.
Miari
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Presti
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ML
Rizzi
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Samanin
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Vezzani
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D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*
D016194:Receptors, N-Methyl-D-Aspartate; C064540:CGP 39551; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C012058:tenocyclidine; D017378:Quinolinic Acid; D007736:Kynurenic Acid; D010622:Phencyclidine; C057013:7-chlorokynurenic acid; D009638:Norepinephrine