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.