ALTERATIONS IN THE BRAIN GABA(A) BENZODIAZEPINE RECEPTOR CHLORIDE IONOPHORE COMPLEX IN A GENETIC MODEL OF PAROXYSMAL DYSTONIA - A QUANTITATIVE AUTORADIOGRAPHIC ANALYSIS/

Dystonia is a relatively common syndrome of sustained muscle contracti ons, 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 g enetically (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 qua ntitative autoradiographic analysis of ligand binding to different sit es of the GABA(A)/benzodiazepine receptor-chloride ionophore complex w as carried out in 123 brain areas from genetically dystonic mutant ham sters and age-matched control hamsters. Animals were killed 2 weeks af ter their last dystonic attack. Analysis of the GABA-binding site of t he receptor complex, using the ligand [H-3]muscimol, and the benzodiaz epine site labelled with [H-3]flunitrazepam revealed no significant al terations in the binding of either ligand in any of the brain regions examined. In contrast, widespread changes were observed in binding den sities of [S-35]t-butylbicyclophosphorothionate binding was found in s everal parts of the thalamus, cortex, and hippocampus as well as in th e red nucleus, the subthalamic nucleus, and the granular layer of the cerebellum. Since high-affinity [S-35]TBPS binding would indicate an i mpaired GABAergic function. The study is consistent with the concept t hat dystonia is caused by impaired connections between the basal gangl ia, the thalamus, and frontal association areas. The data on increased [S-35]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.