Neuronal Adenosine A Receptors Signal Ergogenic Effects of Caffeine

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 and A receptors. We now investigated AR 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 AR knockout (KO) colony ran an incremental exercise test with indirect calorimetry (V̇O and RER). We administered caffeine (15 mg/kg, i.p., nonselective) and SCH 58261 (1 mg/kg, i.p., selective AR 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 V̇Omax, running power, and critical power, showing that AR antagonism is ergogenic. Furthermore, the ergogenic effects of caffeine were abrogated in global and forebrain AR KO mice, showing that the antagonism of AR in forebrain neurons is responsible for the ergogenic action of caffeine. Furthermore, caffeine modified the exercising metabolism in an AR-dependent manner, and AR was paramount for exercise thermoregulation.