Caffeine is one of the most used ergogenic aid for physical exercise and sports. However, its mechanism of action is still controversial. The adenosinergic hypothesis is promising due to the pharmacology of caffeine, a nonselective antagonist of adenosine A(1) and A(2A) receptors. We now investigated A(2A)R as a possible ergogenic mechanism through pharmacological and genetic inactivation. Forty-two adult females (20.0 +/- 0.2 g) and 40 male mice (23.9 +/- 0.4 g) from a global and forebrain A(2A)R knockout (KO) colony ran an incremental exercise test with indirect calorimetry (V.O-2 and RER). We administered caffeine (15 mg/kg, i.p., nonselective) and SCH 58261 (1 mg/kg, i.p., selective A(2A)R antagonist) 15 min before the open field and exercise tests. We also evaluated the estrous cycle and infrared temperature immediately at the end of the exercise test. Caffeine and SCH 58621 were psychostimulant. Moreover, Caffeine and SCH 58621 were ergogenic, that is, they increased V.O(2)max, running power, and critical power, showing that A(2A)R antagonism is ergogenic. Furthermore, the ergogenic effects of caffeine were abrogated in global and forebrain A(2A)R KO mice, showing that the antagonism of A(2A)R in forebrain neurons is responsible for the ergogenic action of caffeine. Furthermore, caffeine modified the exercising metabolism in an A(2A)R-dependent manner, and A(2A)R was paramount for exercise thermoregulation.
