Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function

Korkutata, Mustafa; Saitoh, Tohru; Chérasse, Yoan; Ioka, Shuji; Feng, Duo; Qin, Rujie; Murakoshi, Nobuyuki; Fujii, Shinya; Zhou, Xiao-cong; Sugiyama, Fumihiro; Chen, Jiang‐Fan; Kumagai, Hidetoshi; Nagase, Hiroshi; Lazarus, Michael

doi:10.1016/j.neuropharm.2018.10.022

Cited by 36 publications

(32 citation statements)

References 45 publications

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“…In the case of A 2A R, its role in regulating body temperature is controversial 81 . The selective A 2A R agonist 2-p-(2-carboxyethyl)-phenethylamino-5′-N-ethylcarboxamidoadenosine-hydrochloride (CGS 21680) induces hyperthermia in rats 82 and mice 83 . We now show that SCH 58261 does not change resting and recovery temperature.…”

Section: Discussionmentioning

confidence: 99%

Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

Aguiar

Speck

Canas

et al. 2020

Sci Rep

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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 ...

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Section: Discussionmentioning

confidence: 99%

Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

Aguiar

Speck

Canas

et al. 2020

Sci Rep

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“…This action is effected through adenosine (A)1 inhibitory receptors which are located on neurons of the arousal circuits, including ACh, NA, HA, and Orx neurons, and which have been shown to increase on these neurons with SD [65]. Adenosine also acts upon A2a excitatory receptors identified upon other presumed sleep-promoting neurons [195][196][197]. Accumulation of extracellular adenosine and increases in adenosine receptors during SD would thus effect increasing inhibition of the arousal circuits and excitation of the sleep circuits such as to enhance sleep drive and promote sleep homeostasis.…”

Section: Homeostatic Regulation Of Arousal and Sleep Circuitsmentioning

confidence: 99%

Arousal and sleep circuits

Jones

2019

Neuropsychopharmacol.

164

109

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The principal neurons of the arousal and sleep circuits are comprised by glutamate and GABA neurons, which are distributed within the reticular core of the brain and, through local and distant projections and interactions, regulate cortical activity and behavior across wake-sleep states. These are in turn modulated by the neuromodulatory systems that are comprised by acetylcholine, noradrenaline, dopamine, serotonin, histamine, orexin (hypocretin), and melanin-concentrating hormone (MCH) neurons. Glutamate and GABA neurons are heterogeneous in their profiles of discharge, forming distinct functional cell types by selective or maximal discharge during (1) waking and paradoxical (REM) sleep, (2) during slow wave sleep, (3) during waking, or (4) during paradoxical (REM) sleep. The neuromodulatory systems are each homogeneous in their profile of discharge, the majority discharging maximally during waking and paradoxical sleep or during waking. Only MCH neurons discharge maximally during sleep. They each exert their modulatory influence upon other neurons through excitatory and inhibitory receptors thus effecting a concerted differential change in the functionally different cell groups. Both arousal and sleep circuit neurons are homeostatically regulated as a function of their activity in part through changes in receptors. The major pharmacological agents used for the treatment of wake and sleep disorders act upon GABA and neuromodulatory transmission.

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“…107 It is worth mentioning that the interest of considering the use of A 2A R antagonist as coadjuvants to manage the evolution of epilepsy is particularly attractive in view of the ability of these A 2A R antagonists to control the most common comorbibities with epilepsy, namely memory impairment, [244][245][246][247][248] mood dysfunction, [249][250][251] migrane, 252,253 and sleep disorders. 254,255…”

Section: Strategies For Epilepsy Preventionmentioning

confidence: 99%

Role of Adenosine in Epilepsy and Seizures

Tescarollo

Rombo

DeLiberto

et al. 2020

Journal of Caffeine and Adenosine Research

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Adenosine is an endogenous anticonvulsant and neuroprotectant of the brain. Seizure activity produces large quantities of adenosine, and it is this seizure-induced adenosine surge that normally stops a seizure. However, within the context of epilepsy, adenosine plays a wide spectrum of different roles. It not only controls seizures (ictogenesis), but also plays a major role in processes that turn a normal brain into an epileptic brain (epileptogenesis). It is involved in the control of abnormal synaptic plasticity and neurodegeneration and plays a major role in the expression of comorbid symptoms and complications of epilepsy, such as sudden unexpected death in epilepsy (SUDEP). Given the important role of adenosine in epilepsy, therapeutic strategies are in development with the goal to utilize adenosine augmentation not only for the suppression of seizures but also for disease modification and epilepsy prevention, as well as strategies to block adenosine A 2A receptor overfunction associated with neurodegeneration. This review provides a comprehensive overview of the role of adenosine in epilepsy.

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Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function

Cited by 36 publications

References 45 publications

Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

Arousal and sleep circuits

Role of Adenosine in Epilepsy and Seizures

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