cyclic-gmp and Dystonia

In a hamster model (genetic symbol dt(sz)) of primary paroxysmal non-kinesiogenic dystonic choreoathetosis, recent studies have shown beneficial effects of glutamate and dopamine receptor antagonists. Nitric oxide (NO), synthesized from L-arginine by NO synthase in response to glutamate receptor activation, elicits cyclic GMP and modulates glutamate-mediated processes and striatal dopamine release. Therefore, the effects of NO synthase inhibitors and of L-arginine on severity of dystonia were investigated in dt(sz) hamsters in which dystonic attacks, characterized by twisting movements and postures, can be induced by stress. The NO synthase inhibitors N(G)-nitro-L-arginine (L-NNA), N(G)-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole significantly reduced the severity of dystonia. At antidystonic effective doses neither L-NNA nor L-NAME caused observable side effects, whereas 7-nitroindazole exerted moderate reduction of locomotor activity. The antidystonic effect of L-NAME was reversed by co-administration of the NO precursor L-arginine. However, L-arginine administered alone did not exert any effect on severity of dystonia. Cerebellar cyclic GMP levels in brains of mutant hamsters in comparison to non-dystonic control hamsters did not significantly differ, but the cerebellar cyclic GMP levels tended to be increased in dt(sz) hamsters during a dystonic attack. L-NAME significantly decreased the cerebellar cyclic GMP levels in both dt(sz) and control hamsters. Although an overproduction of NO is probably not critically involved in the pathogenesis of paroxysmal dystonia, it may contribute to the manifestation of dystonic attacks, as indicated by the antidystonic effects of NO synthase inhibitors. Peripheral side effects may limit the clinical use of NO synthase inhibitors, but more selective inhibitors of the neuronal NO synthase should be considered as interesting candidates for the treatment of paroxysmal dystonia.

Topics: Animals; Brain Chemistry; Cricetinae; Cyclic GMP; Dopamine; Dystonia; Enzyme Inhibitors; Indazoles; Motor Activity; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroarginine; Receptors, N-Methyl-D-Aspartate

The research program described here has focused primarily on identifying sites of dysfunction in the central nervous system of rat mutants described as dystonic. The evidence strongly favors the position that there is a defect in the cerebellum of the dt rat. At present it seems reasonable to propose as a working hypothesis that there is a defect in the Purkinje cells that renders these neurons less sensitive to the excitatory neurotransmitters released by the climbing and parallel fibers. The finding that an abnormality in GAD activity in the deep cerebellar nuclei is relatively localized when first detected but spreads over time as the motor syndrome intensifies may indicate that there is a progressive decline in the function of the Purkinje cells. The fact that electrophysiological techniques detect a mixture of relatively normal and abnormal Purkinje cell activity in animals with advanced symptoms is consistent with such a proposal. Finding significant abnormalities in the cerebellum of the dt rat does not necessarily mean that this is the site of the primary defect responsible for the motor syndrome seen in these animals. We have failed to detect any signs of dysfunction in the basal ganglia, the presumed locus of a defect in human torsion dystonia. However, our investigations have been limited almost exclusively to the striatum. Thus, the possibility of defects at other sites, such as the globus pallidus or thalamus must be considered. Although we have not yet demonstrated that the abnormalities detected in the cerebellum are causally related to the behavior of the dt rat, the behavioral syndrome is consistent with a cerebellar defect. It has been suggested that the cerebellum is important for the continuing calibration of coordinated motor behavior. Important observations on the effects of cerebellar lesions have come from the study of the oculomotor system. Lesions in the cerebellum have been shown to eliminate the ability to recalibrate the saccadic eye movement system and to destroy the adaptive plasticity of the vestibulo-ocular reflex A cerebellar defect could result in a failure in motor learning or in the calibration of motor systems that must take place as the rat pup masters adult patterns of locomotion. We note that lesions of the climbing fiber system with 3-AP lead to some of the same biochemical effects seen in dt rats but do not produce an identical behavioral syndrome.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Acetylcholine; Animals; Brain; Catecholamines; Cyclic GMP; Dystonia; Electrophysiology; Glutamate Decarboxylase; Motor Activity; Rats; Rats, Mutant Strains; Serotonin

The dystonic rat (dt) is an autosomal recessive mutant displaying a complex motor syndrome that includes sustained axial twisting movements. The syndrome is correlated with increased glutamic acid decarboxylase activity in the deep cerebellar nuclei and increased cerebellar norepinephrine levels in comparison with phenotypically normal littermates. Biochemical, behavioral, and anatomical techniques were used to investigate the possibility that the abnormalities noted in the cerebellum of the dt rat were indicative of altered function of the major projection neurons of the cerebellar cortex, the Purkinje cells. Phenotypically normal rats showed tremor in response to harmaline, a drug that acts on the inferior olive to produce bursting in the climbing fiber pathway. Dystonic rats were insensitive to the effects of harmaline but did respond to oxotremorine. Levels of the cyclic nucleotide 3',5'-cyclic guanosine monophosphate, a biochemical marker for Purkinje cells, increased in response to harmaline in normal rats but were significantly lower in dystonic rats under both basal and harmaline-stimulated conditions. Purkinje cell soma size was reduced in the dystonic rats but no other morphological correlates of the behavioral or biochemical deficits were noted. Taken together with other observations on this mutant, the results suggest an impairment in the cerebellum or in its connections with lower brainstem and spinal cord sites.

Topics: Alkaloids; Animals; Behavior, Animal; Cerebellum; Cyclic GMP; Drug Resistance; Dystonia; Harmaline; Oxotremorine; Purkinje Cells; Rats; Rats, Mutant Strains; Tremor