Improvement of postural adjustment steps in hemiparkinsonian rats chronically treated with caffeine is mediated by concurrent blockade of A1 and A2A adenosine receptors

Abstract

Chronic treatment with the non-selective adenosine receptor antagonist caffeine produces full recovery of the contralateral adjusting steps in hemiparkinsonian rats. In order to disclose which adenosine receptor subtype mediates this effect, a group of hemiparkinsonian rats (n=9) was treated with caffeine (5.15 mumol/kg/day), or equimolar doses of selective A1 (DPCPX) or A2A (ZM 241385) adenosine receptor antagonists, administered in a counterbalanced order over periods of 3 weeks, interspersed with equivalent washout intervals. Treatment with ZM 241385 caused full recovery (102+/-6%) of the contralateral forepaw stepping, while the maximal effect of DPCPX was only 73+/-7% of that produced by caffeine. The maximal effect of caffeine and ZM 241385 remained stable throughout the treatment period. The response to DPCPX showed more fluctuations, but tolerance did not develop. Stepping improvement was significantly faster with DPCPX than with ZM 241385, while caffeine had intermediate values. Stepping decrease after treatment interruption was faster with ZM 241385 than with caffeine, while DPCPX had intermediate values. In other experiments with the same rats, addition of the A2AR agonist CGS 21680 (5.15 mumol/kg) or the A1R agonist CCPA (2.71 mumol/kg) during the second week of caffeine treatment reversed the improvement of contralateral stepping by 59+/-4% and 30+/-3%, respectively. The combined treatment with CGS 21680 and CCPA caused complete reversal of the contralateral stepping recovery afforded by caffeine, which was more than additive (114+/-5%) compared with the sum of the maximal inhibition produced by either agonist administered alone (89+/-4%). In all cases, after interrupting the adenosine agonists, the effect of caffeine was fully restored. None of the aforementioned treatments induced significant changes in the stepping of the ipsilateral forepaw. Collectively, these results suggest that the improvement of postural adjustments induced by chronic treatment with low doses of caffeine in hemiparkinsonian rats is mediated by concurrent blockade of A1 and A2A adenosine receptors, with a larger involvement of the latter.