Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A ₁ receptors and promotes non-rapid eye movement sleep

Abstract

Adenosine has been proposed to promote sleep through A1 receptors (A 1R's) and/or A2A receptors in the brain. We previously reported that A 2A receptors mediate the sleep-promoting effect of prostaglandin D2, an endogenous sleep-inducing substance, and that activation of these receptors induces sleep and blockade of them by caffeine results in wakefulness. On the other hand, A 1R has been suggested to increase sleep by inhibition of the cholinergic region of the basal forebrain. However, the role and target sites of A1R in sleep-wake regulation remained controversial. In this study, immunohistochemistry revealed that A 1R was expressed in histaminergic neurons of the rat tuberomammillary nucleus (TMN). In vivo microdialysis showed that the histamine release in the frontal cortex was decreased by microinjection into the TMN of N 6 -cyclopentyladenosine (CPA), an A1R agonist, adenosine or coformycin, an inhibitor of adenosine deaminase, which catabolizes adenosine to inosine. Bilateral injection of CPA into the rat TMN significantly increased the amount and the delta power density of non-rapid eye movement (non-REM; NREM) sleep but did not affect REM sleep. CPA-promoted sleep was observed in WT mice but not in KO mice for A 1R or histamine H1 receptor, indicating that the NREM sleep promoted by A 1R-specific agonist depended on the histaminergic system. Furthermore, the bilateral injection of adenosine or coformycin into the rat TMN increased NREM sleep, which was completely abolished by coadministration of 1,3-dimethyl-8-cyclopenthylxanthine, a selective A 1R antagonist. These results indicate that endogenous adenosine in the TMN suppresses the histaminergic system via A 1R to promote NREM sleep.Adenosine deaminase ͉ histamine ͉ knockout mouse ͉ rat I n 1954, Feldberg and Sherwood (1) showed that intraventricular injection of micromole quantities of adenosine into cats caused a state resembling natural sleep of 30-min duration. Subsequent pharmacological studies from several laboratories demonstrated that adenosine and its receptor agonists promoted, but antagonists such as caffeine, inhibited both non-rapid eye movement (non-REM; NREM) and REM sleep (for review, see refs. 2, 3). However, the exact molecular mechanisms underlying sleep-wake regulation by adenosine still remained unclear. Since 1983, we have reported that prostaglandin (PG) D 2 is an endogenous sleep-inducing substance in rodents (4) and monkeys (5). PGD 2 -induced sleep was indistinguishable from natural physiological sleep as judged by several electrophysiological and behavioral criteria (5). Subsequent studies have shown that PGD 2 is involved in both circadian (6, 7) and homeostatic regulation of sleep (8). Further studies on the molecular mechanisms of sleep-wake regulation by PGD 2 demonstrated that PGD 2 is produced by the action of lipocalin-type PGD synthase dominantly expressed in the leptomeninges (9), binds with PGD receptors (DPRs) exclusively localized in the arachnoid membrane of the basal forebrain (BF) (10), and promotes sleep thr...

Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats

“…Another group of animals (n = 6) received DMSO or SB 334867 (0.5 μg) (whichever was not applied on the second day) followed by orexin A (10 pmol) application on day 2 or 4 randomly. by SLEEPSIGN software, according to the methods described previously [23][24][25] .…”

Adenosine inhibits glutamatergic input to basal forebrain cholinergic neurons

“…Adenosine is a purine nucleoside; it is a by-product of ATP hydrolysis and might represent a cellular signal for energy demand in the brain (Benington and Heller 1995;Chagoya de Sanchez et al 1993). Adenosine has been shown to promote slow-wave sleep and rapid eye movement (REM) sleep in cats and rats (Basheer et al 2004;PorkkaHeiskanen et al 2002;Radulovacki 1995;Radulovacki et al 1984) and more recently in mice (Coleman et al 2006;Oishi et al 2008;Urade et al 2003;Van Dort et al 2009). In the early 1990s it was hypothesized that adenosine accumulates in the extracellular space during waking where, on reaching sufficiently high extracellular levels, it could produce sleep through inhibition of wake-active neurons, in particular those of the basal forebrain (BF) (Rainnie et al 1994).…”

Paeoniflorin Promotes Non-rapid Eye Movement Sleep via Adenosine A1 Receptors

“…The R,A 1 R antagonist CPT blocked these effects induced by PF (Liu et al, 2005;Zhang et al, 2009). The R,A 1 R agonist increases sleep after perfusion into the basal forebrain and TMN (Murillo-Rodriguez et al, 2004;Oishi et al, 2008). The unilateral infusion of an R,A 1 Rselective antagonist into the basal forebrain decreased sleep (Strecker et al, 2000).…”

“…The A 1 Rs are widely expressed in the cortex, thalamus, hippocampus, and basal ganglia regions (Thakkar et al, 2002;Huang et al, 2007Huang et al, , 2011Oishi et al, 2008;Lazarus et al, 2013). Oishi et al (2008) reported that R,A 1 R was highly This work was supported in part by grants-in-aid for scientific research from the National Natural Science Foundation of China (81420108015, 81301135, 31171010, 31171049, 31121061, 31271164, J1210041, 31471064, 31421091,81420108015, 31530035), the National Basic Research Program of China (2015CB856401, 2011CB711000), a key laboratory program of the Education Commission of Shanghai Municipality (ZDSYS14005), the Shanghai Committee of Science and Technology (13ZR1403200, 14JC1400900, 13dz2260700, 13140903100), and the Shanghai Leading Academic Discipline Project (B119).…”