Motor stimulant effects of the adenosine A(2A) receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats

Several evidences indicate that the selective blockade of adenosine A(2A) r eceptors counteracts the motor activity impairment in experimental models o f Parkinson's disease. In the present study, the effects of the adenosine A (2A) receptor antagonist, SCH 58261 (5-amino-7-(beta -phenylethyl)-2-(8-fur yl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine, were assessed following a repeated treatment schedule in the contralateral turning behavior rat mo del of Parkinson's disease. Unilateral lesions of the nigrostriatal pathway were induced by injecting g-hydroxydopamine (6-OHDA) in medial forebrain b undle. Repeated administration of SCH 58261 was performed either alone (7 a nd 14 days repeated SCH 58261) or together with L-dopa (19 days repeated SC H 58261 plus L-dopa or L-dopa alone). After a 7- and 14-day repeated admini stration schedule, SCH 58261 (5 mg/kg) maintained its ability to potentiate the contralateral turning behavior induced by a subthreshold dose of L-dop a (2 mg/kg i.p.), showing no tolerance to its stimulant effects. SCH 58261 (5 mg/kg) plus L-dopa (3 mg/kg) or L-dopa (6 mg/kg) alone induced, at these dosages, the same number of contralateral turnings after the first adminis tration. While chronic intermittent SCH 58261 plus L-dopa did not lead to a modified turning behavior during treatment, L-dopa alone produced a progre ssive increase in turning behavior intensity and duration. These results pr ovide evidence that SCH 58261 retains its ability to potentiate L-dopa effe cts in a validated rat model of Parkinson's disease even after repeated tre atments. Moreover, these results suggest that adenosine A(2A) blockade prev ents the appearance of motor response alterations in L-dopa-treated rats, s upporting the concept that A(2A) receptor antagonists have a therapeutic po tential for the treatment of Parkinson's disease. (C) 2001 Wiley-Liss, Inc.