Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

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 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 (Vȯ 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 Vȯ 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. The natural plant alkaloid caffeine (1,3,7-trimethylxantine) is one of the most common ergogenic substances for physical activity practitioners and athletes 1-10. Caffeine increases endurance 1,8-12 , intermittent 7,13,14 and resistance 4,15 exercise in humans. In rodents, its ergogenic effects are conserved because caffeine increases running time on the treadmill at constant 16,17 and accelerated speeds 18,19. Sports sciences promote nonselective phosphodiesterase (PDE) inhibition 7,8 and increased calcium mobilization 2,7,8 as mechanisms for these ergogenic effects. However, the primary pharmacological effect of caffeine is the nonselective antagonism of adenosine A 1 and A 2A receptors (A 1 R, A 2A R) 20-23. Adenosine can act as an inhibitory modulator of the Central Nervous System (CNS) associated with tiredness and drowsiness 24-29. During exercise, circulating ADP/AMP/adenosine levels increase due to ATP hydrolysis 30,31. However, there is still no substantial evidence on the role of adenosine in exercise-induced fatigue. It is just known that the nonselective A 1 R and A 2A R agonist 5′-(N-ethylcarboxamido)adenosine (NECA), injected into the rat brain, abolishes the ergogenic effects of caffeine 16. Since there is increasing evidence that the adenosine modulation system critically controls allostasis 29 and A 2A R 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 A 2A R in the CNS. We combined the use of pharmacology (SCH 58261 and caffeine) and transgenic mice with tissue-selective deletion ...

Deletion of CD73 increases exercise power in mice

“…Acute exercise increases adenosine levels in human blood [ 2 , 3 ] and the rat brain [ 4 ]. Accordingly, adenosine contributes to exercise-induced vasodilation [ 5 ] and also causes drowsiness and tiredness at rest, being a candidate molecule to signal exercise fatigue [ 6 – 8 ]. The non-selective adenosine receptor antagonist, caffeine, is well-established to cause an ergogenic effect [ 8 , 9 ], which is mimicked by selective antagonists of adenosine A 2A receptors (A 2A R), abrogated in forebrain A 2A R knockout mice [ 8 ], and eliminated upon administration of the A 2 R agonist NECA [ 6 , 10 ].…”

“…Accordingly, adenosine contributes to exercise-induced vasodilation [ 5 ] and also causes drowsiness and tiredness at rest, being a candidate molecule to signal exercise fatigue [ 6 – 8 ]. The non-selective adenosine receptor antagonist, caffeine, is well-established to cause an ergogenic effect [ 8 , 9 ], which is mimicked by selective antagonists of adenosine A 2A receptors (A 2A R), abrogated in forebrain A 2A R knockout mice [ 8 ], and eliminated upon administration of the A 2 R agonist NECA [ 6 , 10 ]. These observations strongly imply central A 2A R as critical regulators of the impact of adenosine on exercise performance, whereas there is no consistent evidence for the involvement of A 1 , A 2B , or A 3 receptors in the control of exercise performance.…”

Exercise decreases aberrant corticostriatal plasticity in an animal model of l-DOPA-induced dyskinesia

“…The incremental protocol started at 10 cm/s with an increment of 5 cm/s every 2 min at a slope of 5 . The exercise test lasted until running exhaustion, defined by the animal's inability to leave the electrical grid (0.2 mA) for 5 s (18,19).…”

“…V _ O 2peak was estimated during treadmill running in a metabolic chamber (Gas Analyzer ML206, 23 Â 5 Â 5 cm, AD Instruments, Harvard) coupled to the treadmill (18). Mice remained in the chamber for 15 min before exercise testing.…”

“…Atmospheric air ($21% O 2 and $0.03% CO 2 ) was renewed at a rate of 120 mL/min, using the same sampling rate for the LASER oxygen sensor (Oxigraf X2004, resolution 0.01%). Power output was estimated based on a standard conversion of the vertical work, body weight, and running speed (18,19), where power is the first derivative of work relative to time (run time at each stage). All the mice had a working range similar to the naive mice already reported in previous studies (18,19).…”