Decreased adenosine receptor binding in dystonic brains of the dt(sz) 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 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, [(3)H]DPCPX (8-cyclopentyl-1,3-dipropylxanthine) binding to adenosine A(1) receptors and [(3)H]CGS 21680 (2p-(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.
Nobrega
J N
JN
Neuroimaging Research Section, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8 Canada.
Barlow
K L
KL
Raymond
R
R
Richter
A
A
D000818:Animals; D030801:Animals, Genetically Modified; D001345:Autoradiography / Q000379:methods; D006224:Cricetinae; D004195:Disease Models, Animal; D020821:Dystonic Disorders / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D014316:Tritium / Q000493:pharmacokinetics; D014970:Xanthines / Q000493:pharmacokinetics
D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; D014316:Tritium; C051360:1,3-dipropyl-8-cyclopentylxanthine