Lack of tolerance to motor stimulant effects of a selective adenosine A(2A) receptor antagonist

It is well known that tolerance develops to the actions of caffeine, which acts as an antagonist on adenosine A(1) and A(2A) receptors. Since selectiv e adenosine A(2A) antagonists have been proposed as adjuncts to 3,4-dihydro xyphenylalanine (L-DOPA) therapy in Parkinson's disease we wanted to examin e if tolerance also develops to the selective A(2A) receptor antagonist 5-a mino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]- 1,2,4-triazolo [1,5-c] pyrimidine (SCH 58261). SCH 58261 (0.1 and 7.5 mg/kg) increased basal locom otion and the motor stimulation afforded by apomorphine. Neither effect was subject to tolerance following long-term treatment with the same doses giv en intraperitoneally twice daily. There were no adaptive changes in A(1) an d A(2A) adenosine receptors or their corresponding messenger RNA or in dopa mine D-1 or D-2 receptors. These results demonstrate that the tolerance tha t develops to caffeine is not secondary to its inhibition of adenosine A(2A ) receptors. The results also offer hope that long-term treatment with an a denosine A(2A) receptor antagonist may be possible in man. (C) 2000 Elsevie r Science B.V. All rights reserved.