ABSTRACT
It was shown in the present study that three antagonists of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor, including 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) and 6-(1H-imidazole-1-yl)-7-nitro-2,3-(1H, 4H)-quinoxalinedione (YM90K), caused marked reversal of akinesia when administered into the entopeduncular nucleus of rats rendered parkinsonian by bilateral substantia nigra pars compacta lesion. These data suggest that centrally active AMPA antagonists may have therapeutic utility in the treatment of idiopathic Parkinson's disease.
Subject(s)
Anti-Anxiety Agents , Motor Activity/drug effects , Parkinson Disease, Secondary/psychology , Receptors, AMPA/antagonists & inhibitors , Animals , Benzodiazepines/administration & dosage , Benzodiazepines/pharmacology , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/pharmacology , Male , Mesencephalon/physiology , Microinjections , Oxidopamine , Parkinson Disease, Secondary/chemically induced , Quinoxalines/administration & dosage , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Substantia Nigra/physiologyABSTRACT
It was shown in the present study that several structurally diverse antagonists of the glycine site of the NMDA receptor, including (R)-HA-966, L689,560, 5,7-dichlorokynurenic acid, 7-chlorokynurenic acid, and two of ZENECA's novel pyridazinoindole glycine antagonists, caused marked reversal of akinesia when administered intrastriatally to monoamine depleted mice. Coinjection of the glycine agonist D-serine antagonized this locomotor stimulation. In addition, all glycine antagonists tested did not cause significant locomotor stimulation when intrastriatally administered to normal mice. These data suggest that glycine antagonists may offer therapeutic utility in the treatment of idiopathic Parkinson's disease.
