Decreased adenosine receptor binding in dystonic brains of the dtsz mutant

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 A1/A2A receptors. In the dtsz mutant hamster, a model of this movement disorder, adenosine A1 receptor antagonists were previously found to worsen dystonia, while adenosine A1 and A2A receptor agonists exerted pronounced beneficial effects. Therefore, in the present study, adenosine receptor A1 and A2A binding was determined by autoradiographic analyses in dtsz 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 A1 receptors and [3H]CGS 21680 (2p-(2carboxyethylphen-ethylamino-5′-N-ethlycarboxamindoadenosine) binding to adenosine A2A receptors were significantly lower throughout the brain of dystonic animals. Under normal resting conditions, mutant hamsters showed significant decreases in adenosine A1 (−12 to−42%) and in A2A (−19 to−34%) receptor binding compared with controls. Stressful stimulation increased adenosine A1 and A2A 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 A1 and A2A receptor agonists and of striatal dysfunctions in the dtsz mutant, the reduced adenosine receptor binding may be an important factor in the pathogenesis of paroxysmal dystonia.