Regionally selective and age-dependent alterations in benzodiazepine receptor binding in the genetically dystonic hamster.
Previous pharmacological studies have indicated that impairment of GABAergic transmission may be involved in the pathophysiology of dystonia in the mutant dtsz hamster, i.e., a genetic animal model for idiopathic dystonia. In the present experiments, the kinetic constants of [3H]flumazenil binding to the benzodiazepine site of the GABAA receptor were calculated from equilibrium binding measurements in various brain regions of genetically dystonic hamsters and age-matched controls. Because dystonia in mutant dtsz hamsters is transient and disappears after approximately 60-70 days of age, [3H]flumazenil binding was studied at the age of maximum severity of dystonia (30-40 days) and after disappearance of the disease, to examine which neurochemical changes were related to dystonia. In mutant hamsters with the maximum severity of dystonia, receptor affinity of [3H]flumazenil was increased in olfactory bulb, striatum, tectum, and cerebellum, as exemplified by significantly decreased dissociation constants (KD) in these regions. An increased number of binding sites (Bmax) were seen in striatum and frontal cortex but not in the other eight regions studied in this regard. All these changes in [3H]flumazenil binding disappeared in parallel with dystonia, implicating a causal relationship between altered benzodiazepine receptor binding and dystonia in mutant dtsz hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)
Pratt
G D
GD
Institute of Pharmacology, University of Zurich, Switzerland.
Richter
A
A
Möhler
H
H
Löscher
W
W
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics* / Q000378:metabolism*; D005442:Flumazenil / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D007700:Kinetics; D009154:Mutation; D009830:Olfactory Bulb / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D013477:Superior Colliculi / Q000378:metabolism; D014316:Tritium
D011963:Receptors, GABA-A; D014316:Tritium; D005442:Flumazenil