Purine Molecules as Hypnogenic Factors Role of Adenosine, ATP, and Caffeine

M.      Diaz-Munoz; R.      Salin-Pascual

Abstract

Purines are ubiquitous molecules with important roles in the regulation of metabolic networks and signal transduction events. In the central nervous system, adenosine and ATP modulate the sleep-wake cycle, acting as ligands of specific transmembrane receptors and as allosteric effectors of key intracellular enzymes for brain energy expenditure. Two types of adenosine receptors seem to be relevant to the sleep function, A1 and A2A. Caffeine, an antagonist of adenosine receptors, has been used as a tool in some of the studies reviewed in the present chapter. Possible changes in adenosine functioning due to the aging process have been observed in animal models and abnormalities in the adenosine system could also explain primary insomnia or the reduced amount of delta sleep and increased sensitivity to caffeine in some subjects with sleep deficits. Caffeine is a methylated-derivate of xanthine with profound effects on the onset and quality of sleep episodes. This purine acts principally as an antagonist of the A2A receptors. Adenosine and ATP in the nervous system are the bridge between metabolic activity, recovery function, and purinergic transmission that underlies the daily wake-sleep cycle in mammals. Modulators of purine actions have the potential to alleviate insomnia and other sleep disorders based on their physiopathological role during the sleep process.

Keywords: Purinergic system, nucleoside, nucleotide, methylxanthine, rapid eye movements, slow-wave sleep, sleep-wake cycle, Purines, ubiquitous molecules, adenosine, ATP, Caffeine, adenosine receptors, insomnia, xanthine, hypoxanthine, Euterpe oleracea, S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), allosteric effector, methylxanthines, neuroprotection, neurodegeneration, angiogenesis, ionotropic (P2X), metabotropic (P2Y), diacylglycerol, crystallography, nociception, G-coupled proteins, lysophosphatidic acid, ryanodine receptor, preoptic area (POA), rapid eye movement (REM), glutamate-, norepinephrine (NE), dopamine (DA), 5-hydroxy-tryptamine (5-HT), hypocretins (orexins), acetylcholine (ACh), slow-wave sleep (SWS), paradoxical sleep (PS), laterodorsal tegmental nuclei (LDT), ventrolateral preoptic area of the hypothalamus (VLPO), N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ), obstructive sleep apnea (OSA), total sleep deprivation (TSD), multiple sleep latency test (MSLT), nitro benzyl-thio-inosine (NBTI), lateral pre-optic area (LPOA), basal forebrain (BF), cholinergic neurons, ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), interleukin-1β, 2,4-dinitrophenol (DNP), glycolytic activity