Dystonia is a relatively common syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The most frequent type of dystonia is idiopathic generalized dystonia, whose pathophysiology is largely unknown. In this respect, mutant animal strains with inborn dystonia may be helpful to elucidate the pathophysiological defects involved in idiopathic dystonia. The genetically dystonic (dt sz ) hamster is an animal model of paroxysmal dystonia that displays attacks of generalized dystonia either spontaneously or in response to mild environmental stimuli. In the present study, a quantitative autoradiographic analysis of ligand binding to different sites of the GABA A /benzodiazepine receptor-chloride ionophore complex was carried out in 123 brain areas from genetically dystonic mutant hamsters and age-matched control hamsters. Animals were killed 2 weeks after their last dystonic attack. Analysis of the GABA-binding site of the receptor complex, using the ligand [ 3 H]muscimol, and the benzodiazepine site labelled with [ 3 H]flunitrazepam revealed no significant alterations in the binding of either ligand in any of the brain regions examined. In contrast, widespread changes were observed in binding densities of [ 35 S] t-butylbicyclophosphorothionate ([ 35 S] t-butylbicyclophosphorothionate), which labels the picrotoxinin site of the GABA A receptor-chloride ionophore complex. Significantly increased [ 35 S] t-butylbicyclophosphorothionate binding was found in several parts of the thalamus, cortex, and hippocampus as well as in the red nucleus, the subthalamic nucleus, and the granular layer of the cerebellum. Since high-affinity [ 35 S]TBPS binding is thought to represent the closed conformation of the GABA-gated chloride ionophore, increased TBPS binding would indicate an impaired GABAergic function.The study is consistent with the concept that dystonia is caused by impaired connections between the basal ganglia, the thalamus, and frontal association areas. The data on increased [ 35 S]TBPS binding are the first evidence implicating alterations in the GABA-gated chloride ion channel function in a movement disorder, i.e. idiopathic generalized dystonia.
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