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

Eur J Pharmacol. 2000 Oct 20;406(3):345-54. doi: 10.1016/s0014-2999(00)00682-8.


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 selective adenosine A(2A) antagonists have been proposed as adjuncts to 3,4-dihydroxyphenylalanine (L-DOPA) therapy in Parkinson's disease we wanted to examine if tolerance also develops to the selective A(2A) receptor antagonist 5-amino-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 locomotion and the motor stimulation afforded by apomorphine. Neither effect was subject to tolerance following long-term treatment with the same doses given intraperitoneally twice daily. There were no adaptive changes in A(1) and A(2A) adenosine receptors or their corresponding messenger RNA or in dopamine D(1) or D(2) receptors. These results demonstrate that the tolerance that 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 adenosine A(2A) receptor antagonist may be possible in man.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apomorphine / pharmacology
  • Caffeine / pharmacology
  • Drug Tolerance
  • Genes, Immediate-Early / drug effects
  • Male
  • Motor Activity / drug effects*
  • Purinergic P1 Receptor Antagonists*
  • Pyrimidines / pharmacology*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine / analysis
  • Receptors, Dopamine / drug effects
  • Receptors, Dopamine / genetics
  • Receptors, Purinergic P1 / analysis
  • Receptors, Purinergic P1 / drug effects
  • Triazoles / pharmacology*


  • 5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine
  • Purinergic P1 Receptor Antagonists
  • Pyrimidines
  • RNA, Messenger
  • Receptors, Dopamine
  • Receptors, Purinergic P1
  • Triazoles
  • Caffeine
  • Apomorphine