EFFECTS OF 7-NITROINDAZOLE, N-G-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 neu ronal nitric oxide (NO) synthase mediates the abnormal consequences of increased NMDA receptor-mediated synaptic transmission in models of p ostural tremor, Parkinson's disease and epilepsy. We used 7-nitroindaz ole, a selective inhibitor of neuronal NO synthase, and N-G-nitro-L-ar ginine (L-NAME), an unspecific NO synthase inhibitor, and compared the ir action with that of the competitive NMDA receptor antagonist -2-car boxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid (D-CPPene). In both mice and rats, 7-nitroindazole, L-NAME and D-CPPene dose dependently r eversed 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 equip otent in preventing harmaline-induced cGMP increase. Harmaline-induced tremor in mice and mts was suppressed by D-CPPene, but not by 7-nitro indazole or by L-NAME. This effect of D-CPPene was not due to unspecif ic suppression of motor activity, since D-CPPene did not affect locomo tor activity at doses which reduced tremor. D-CPPene, but not 7-nitroi ndazole and L-NAME potentiated the antiparkinsonian action of the dopa mine agonist lisuride in rats with unilateral 6-hydroxydopamine lesion s of the substantia nigra, D-CPPene antagonized seizures induced by in tracerebroventricular injection of NMDA in mice. In contrast, 7-nitroi ndazole and L-NAME had only a tendency to prevent seizures and to dela y the latency to onset of seizures. We conclude from these results tha t neuronal NO synthase does not serve as a major mediator of increased NMDA receptor-mediated synaptic transmission in animal models of Park inson's disease, postural tremor and epilepsy. The novel observation t hat D-CPPene suppresses harmaline-induced tremor leads us to suggest t hat NMDA receptor antagonists should be considered as novel therapeuti cs for postural tremor.