Abstract
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 A1 and A2A receptors. We now investigated A2AR 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 A2AR knockout (KO) colony ran an incremental exercise test with indirect calorimetry (V̇O2 and RER). We administered caffeine (15 mg/kg, i.p., nonselective) and SCH 58261 (1 mg/kg, i.p., selective A2AR 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 V̇O2max, running power, and critical power, showing that A2AR antagonism is ergogenic. Furthermore, the ergogenic effects of caffeine were abrogated in global and forebrain A2AR KO mice, showing that the antagonism of A2AR in forebrain neurons is responsible for the ergogenic action of caffeine. Furthermore, caffeine modified the exercising metabolism in an A2AR-dependent manner, and A2AR was paramount for exercise thermoregulation.
Highlights
Caffeine is one of the most used ergogenic aid for physical exercise and sports
Since there is increasing evidence that the adenosine modulation system critically controls allostasis[29] and A2AR have a crucial role in the ability of caffeine to normalize brain function[30], we hypothesized that caffeine decreases fatigue during exercise through antagonism of A2AR in the Central Nervous System (CNS)
We have demonstrated that A2AR antagonism is a mechanism of action for ergogenicity, as SCH 58261 was ergogenic
Summary
Caffeine is one of the most used ergogenic aid for physical exercise and sports. its mechanism of action is still controversial. We administered caffeine (15 mg/kg, i.p., nonselective) and SCH 58261 (1 mg/kg, i.p., selective A2AR antagonist) 15 min before the open field and exercise tests. The ergogenic effects of caffeine were abrogated in global and forebrain A2AR KO mice, showing that the antagonism of A2AR in forebrain neurons is responsible for the ergogenic action of caffeine. Since there is increasing evidence that the adenosine modulation system critically controls allostasis[29] and A2AR have a crucial role in the ability of caffeine to normalize brain function[30], we hypothesized that caffeine decreases fatigue during exercise through antagonism of A2AR in the CNS. We combined the use of pharmacology (SCH 58261 and caffeine) and transgenic mice with tissue-selective deletion of A 2AR, to test this hypothesis in an incremental running test with indirect calorimetry (or ergospirometry). Our goal is to assess the ergogenicity of A 2AR using the pharmacological and genetic tools described above
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