Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions.
The present behavioral study was undertaken to investigate whether neuronal nitric oxide (NO) synthase mediates the abnormal consequences of increased NMDA receptor-mediated synaptic transmission in models of postural tremor, Parkinson's disease and epilepsy. We used 7-nitroindazole, a selective inhibitor of neuronal NO synthase, and NG-nitro-L-arginine (L-NAME), an unspecific NO synthase inhibitor, and compared their action with that of the competitive NMDA receptor antagonist 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid (D-CPPene). In both mice and rats, 7-nitroindazole, L-NAME and D-CPPene dose dependently reversed the harmaline-induced increase of cerebellar cyclic guanosine-5'-monophosphate (cGMP) levels. For subsequent behavioral experiments we used doses of 7-nitroindazole, L-NAME and D-CPPene which were equipotent in preventing harmaline-induced cGMP increase. Harmaline-induced tremor in mice and rats was suppressed by D-CPPene, but not by 7-nitroindazole or by L-NAME. This effect of D-CPPene was not due to unspecific suppression of motor activity, since D-CPPene did not affect locomotor activity at doses which reduced tremor. D-CPPene, but not 7-nitroindazole and L-NAME potentiated the antiparkinsonian action of the dopamine agonist lisuride in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. D-CPPene antagonized seizures induced by intracerebroventricular injection of NMDA in mice. In contrast, 7-nitroindazole and L-NAME had only a tendency to prevent seizures and to delay the latency to onset of seizures. We conclude from these results that neuronal NO synthase does not serve as a major mediator of increased NMDA receptor-mediated synaptic transmission in animal models of Parkinson's disease, postural tremor and epilepsy. The novel observation that D-CPPene suppresses harmaline-induced tremor leads us to suggest that NMDA receptor antagonists should be considered as novel therapeutics for postural tremor.
Department of Neurology, University of Tübingen, Germany.
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Eblen
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Löschmann
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Wüllner
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Turski
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Klockgether
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006246:Harmaline; D006892:Hydroxydopamines; D007191:Indazoles / Q000494:pharmacology*; D008090:Lisuride; D008124:Locomotion / Q000187:drug effects; D008297:Male; D016202:N-Methylaspartate; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D006892:Hydroxydopamines; D007191:Indazoles; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; C065286:SDZ EAA 494; D019335:Nitroarginine; D016202:N-Methylaspartate; D006246:Harmaline; D008090:Lisuride; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; C080122:7-nitroindazole