REGIONALLY SELECTIVE AND AGE-DEPENDENT ALTERATIONS IN BENZODIAZEPINE RECEPTOR-BINDING IN THE GENETICALLY DYSTONIC HAMSTER

Previous pharmacological studies have indicated that impairment of GAB Aergic transmission may be involved in the pathophysiology of dystonia in the mutant dt(sz) hamster, i.e., a genetic animal model for idiopa thic dystonia. In the present experiments, the kinetic constants of [H -3]flumazenil binding to the benzodiazepine site of the GABA(A) recept or were calculated from equilibrium binding measurements in various br ain regions of genetically dystonic hamsters and age-matched controls. Because dystonia in mutant dt(sz) hamsters is transient and disappear s after similar to 60-70 days of age, [H-3]flumazenil binding was stud ied at the age of maximum severity of dystonia (30-40 days) and after disappearance of the disease, to examine which neurochemical changes w ere related to dystonia, In mutant hamsters with the maximum severity of dystonia, receptor affinity of [H-3]flumazenil was increased in olf actory bulb, striatum, tectum, and cerebellum, as exemplified by signi ficantly decreased dissociation constants (K-D) in these regions, An i ncreased number of binding sites (B-max) were seen in striatum and fro ntal cortex but not in the other eight regions studied in this regard. All these changes inz [H-3]-flumazenil binding disappeared in paralle l with dystonia, implicating a causal relationship between altered ben zodiazepine receptor binding and dystonia in mutant dt(sz) hamsters. I n view of the antidystonic effect of benzodiazepines, such as diazepam , and recent neurochemical findings indicating impaired function of th e GABA-gated Cl- channel in dystonic hamsters, the present data might be interpreted as up-regulation of benzodiazepine receptors in respons e to impaired GABAergic function. Furthermore, the present data repres ent the first evidence that GABA(A) receptors are altered in the basal ganglia in idiopathic (primary) dystonia.