Decreased adenosine receptor binding in dystonic brains of the dtsz mutant

Abstract

In patients with paroxysmal non-kinesigenic dyskinesias, episodes of dystonia can be provoked by stress and also by methylxanthines (e.g. caffeine), which inhibit adenosine A 1/A 2A receptors. In the dt sz mutant hamster, a model of this movement disorder, adenosine A 1 receptor antagonists were previously found to worsen dystonia, while adenosine A 1 and A 2A receptor agonists exerted pronounced beneficial effects. Therefore, in the present study, adenosine receptor A 1 and A 2A binding was determined by autoradiographic analyses in dt sz hamsters under basal conditions, i.e. in the absence of a dystonic attack, and in a group of mutant hamsters which exhibited severe stress-induced dystonic attacks prior to kill. In comparison with non-dystonic control hamsters, [ 3H]DPCPX (8-cyclopentyl-1,3-dipropylxanthine) binding to adenosine A 1 receptors and [ 3H]CGS 21680 (2 p-(2carboxyethylphen-ethylamino-5′- N-ethlycarboxamindoadenosine) binding to adenosine A 2A receptors were significantly lower throughout the brain of dystonic animals. Under normal resting conditions, mutant hamsters showed significant decreases in adenosine A 1 (−12 to−42%) and in A 2A (−19 to−34%) receptor binding compared with controls. Stressful stimulation increased adenosine A 1 and A 2A receptor binding in almost all brain regions in both control and dystonic hamsters. The stress-induced increase was more marked in mutant hamsters, leading to a disappearance of differences in most regions compared with stimulated controls, except the striatum. In view of previous findings of striking beneficial effects of adenosine A 1 and A 2A receptor agonists and of striatal dysfunctions in the dt sz mutant, the reduced adenosine receptor binding may be an important factor in the pathogenesis of paroxysmal dystonia.