A. Richter et M. Hamann, Effects of adenosine receptor agonists and antagonists in a genetic animalmodel of primary paroxysmal dystonia, BR J PHARM, 134(2), 2001, pp. 343-352
1 Recent studies have shown beneficial effects of an adenosine A(2A) recept
or agonist in dt(sz) mutant hamsters, an animal model of paroxysmal dystoni
a, in which stress and consumption of coffee can precipitate dystonic attac
ks. This prompted us to examine the effects of adenosine receptor agonists
and antagonists on severity of dystonia in dt(sz) hamsters in more detail.
2 The non-selective adenosine A(1)/A(2A) receptor antagonists, caffeine (10
-20 mg kg(-1) i.p.) and theophylline (10-30 mg kg(-1) s.c.), worsened the d
ystonia in dt(sz) hamsters.
3 Aggravation of dystonia was also caused by the selective adenosine A(1)A(
2A) antagonist CGS 15943 (9-chloro2-2-furyl)[1,2,4]triazolo[1,5-c]quinazoli
n-5-amine) at a dose of 30 mg kg(-1) i.p. and by the adenosine A(1) antagon
ist DPCPX (8-cyclopentyl-1,3-dipropylxanthine; 20-30 mg kg(-1) i.p.), while
the A(2) antagonist DMPX (3,7-dimethyl-1-propargylxanthine; 2 - 4 mg kg(-1
) i.p.) and the highly selective A(2A) antagonist ZM 241385 (4-(2-[7-amino-
2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol; 2 -
5 mg kg(-1) i.p.) failed to exert any effects on dystonia.
4 In contrast to the antagonists, both the adenosine A(1) receptor agonist
CPA (N-6-cyclopentyladenosine; 0.1 - 1.0 mg kg(-1) i.p.) and the A(2A) agon
ist CGS 21680 (2p-(2carboxyethylphen-ethylamino-5 ' -N-ethylcarboxamindoade
nosine; 0.1 - 2.0 mg kg(-1), i.p.) exerted a striking improvement of dyston
ia.
5 These data suggest that the precipitating effects of methylxanthines are,
at least in part, related to their adenosine receptor antagonistic action.
6 Although adenosine receptor agonists can be regarded as interesting candi
dates for the therapy of paroxysmal dystonia, adverse effects may limit the
therapeutic potential of adenosine A(1) agonists, while beneficial effects
of the adenosine A(2A) agonist CGS 21680 were already found at well tolera
ted doses.