Sleep adenosine

In addition, adenosine is implicated in sleep regulation. During periods of extended wakefulness, extracellular adenosine levels rise as a result of metabolic activity in the brain, and this increase promotes sleepiness. During sleep, adenosine levels fall. Caffeine promotes wakefulness by blocking the interaction of extracellular adenosine with its neuronal receptors. ... 

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

Caffeine binds to adenosine receptors in the brain, preventing adenosine from inducing sleep or opening blood vessels. Caffeine also increases levels of dopamine, the neurotransmitter associated with pleasure. This is the chemical mechanism for addiction. The response to adenosine competition causes increased adrenaline flow. 

It is perhaps not surprising that, sinee adenosine has been presented as an endogenous inhibitor of neuronal funetion with its antagonists, like theophylline, being stimulants (see Chapter 13), it should have been implieated in sleep induetion. 

There is also support for a role of PGD2 in sleep control and homeostasis (Hayaishi, 2002). PGD2 is synthesized in the subarachnoid space ventral to the POA. Administration of PGD2 in the subarachnoid space induces normal sleep, and inhibition of synthesis or receptors suppresses sleep. Sleep rebound after deprivation is reduced in mice in which the synthetic enzyme is knocked out. Administration of PGD2 to the subarachnoid space also induces c-Fos in the VLPO as well as dorsal POA neurons (Scammel et a ., 1998). The hypnogenic actions of PGD2 seem to be mediated by an adenosine A2a pathway (Satoh et al, 1966). 

Methippara, M. M., Kumar, S., Alam, Md. N., Szymusiak, R., 8r McGinty, D. (2005). Effects on sleep of microdialysis of adenosine A1 and A2A receptor analogs into the lateral preoptic area of rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, 1715-23. 

Porkka-Heiskanen, T., Alanko, L., Kalinchuk, A., Stenberg, D. (2002). Adenosine and sleep. Sleep Med. Revis 6, 321-32. 

Satoh, S., Matsumura, H., Suzuki, F., Hayaishi, O. (1966). Promotion of sleep mediated by the A2a adenosine receptor and possible involvement of this receptor in the sleep induced by prostaglandin D2 in rats. Proc. Natl Acad. Sci. USA 93, 5980-4. 

Porkka-Heiskanen, T., Strecker, R. E., Thakkar, M. el al (1997). Adenosine a mediator of the sleep-inducing effects of prolonged wakefulness. Science 276, 1265-8. 

Scammell, T. E., Gerashchenko, D. Y., Mochizuki, T. et al. (2001). An adenosine A2a agonist increases sleep and induces Fos in ventrolateral preoptic neurons. 

Coleman, C. G., Baghdoyan, H. A. 8r Lydic, R. (2006). Dialysis delivery of an adenosine A2A agonist into the pontine reticular formation of C57BL/6J mouse increases pontine acetylcholine release and sleep. J. Neurochem. 96, 1750-9. 

Marks, G. A., Shaffery, J. P., Speciale, S. G. Birabil, C. G. (2003). Enhancement of rapid eye movement sleep in the rat by actions at Al and A2A adenosine receptor subtypes with a differential sensitivity to atropine. Neuroscience 116, 913-20. 

One of the distinctive features of TMN neurons is that they contain high levels of adenosine deaminase, a key enzyme involved in deamination of adenosine, a mediator of homeostatic sleep regulation (Thakkar et al, 2003a, b). 

Infusion of prostaglandin D2 (200 pmol/min) or the adenosine A2a receptor agonist CGS21680 (20 pmol/min) for 2 h into the subarachnoid space under the BF, during the dark period, increased NREM sleep and reduced c-Fos protein in the TMN of rats when compared with saline-treated controls (Scammell et al., 1998, 2001). In contrast, infusion of the adenosine Ai receptor agonist N6-cyclopentyl-adenosine (2 pmol/min) in the same area did not have any effect on sleep-wakefulness or c-fos expression in the TMN. 

Adenosine has been proposed to induce sleep by inhibiting cholinergic neurons of the BFB and the brainstem. In this respect, adenosine and the adenosine transport inhibitor NBTI decrease the discharge rate of BFB neurons during W, whereas the adenosine Ai receptor antagonist CPDX induces the opposite effects (Alam et al., 1999 Strecker et al., 2000). In addition, perfusion of adenosine into... 

Sleep-active neurons have been identified in the ventrolateral and medial preoptic areas. These neurons exhibit increased discharge during SWS and REMS rather than W. Sleep-active neurons colocalize GABA and are excited by adenosine and prostaglandin D2 (McGinty Szymusiak, 2001) (Table 9.3). 

Monti, J. M., Jantos, H. Monti, D. (2001). Increase of waking and reduction of NREM and REM sleep after nitric oxide synthase inhibition prevention with GABAa or adenosine Ai receptor agonists. Behav. Brain Res. 123, 23-35. 

Pharmacological experiments have shown that adenosine and its receptor agonists promote, whereas its antagonists inhibit, sleep. Early experiments showed that injection into the cerebral ventricles of 2 pmol (0.5 mg) adenosine... 

Despite theoretical and experimental indications that adenosine has hypno-genic effects, it was necessary, in order to postulate adenosine as a homeostatic sleep factor, to show that its concentration in vivo depends on previous wakefulness and sleep, and to explain the mechanism of its hypnogenic effect. 

Figure 12.1 Extracellular adenosine concentrations in different brain areas, measured with in vivo microdialysis from cats during sleep deprivation (6 h gentle handling) and recovery sleep. Concentrations are given as a percentage of pre-deprivation values. BF, basal forebrain CX, cingulate cortex TH, VA/VL nucleus of thalamus POA, preoptic hypothalamic area DRN, dorsal raphe nucleus PPT, pedunculopontine nucleus. In BF and CX adenosine rises during sleep deprivation, but starts to decline during deprivation in CX, whereas the decline occurs during recovery in the BF. In other areas there is no accumulation during sleep deprivation. Modified from Porkka-Heiskanen et al. (2000).

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