title: Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep.
abstract: Adenosine has been proposed to promote sleep through A(1) receptors (A(1)R's) and/or A(2A) receptors in the brain. We previously reported that A(2A) receptors mediate the sleep-promoting effect of prostaglandin D(2), 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(1)R has been suggested to increase sleep by inhibition of the cholinergic region of the basal forebrain. However, the role and target sites of A(1)R in sleep-wake regulation remained controversial. In this study, immunohistochemistry revealed that A(1)R 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 A(1)R 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(1)R or histamine H(1) receptor, indicating that the NREM sleep promoted by A(1)R-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(1)R antagonist. These results indicate that endogenous adenosine in the TMN suppresses the histaminergic system via A(1)R to promote NREM sleep.
authors.affiliation: Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Oishi
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Huang
authors.forename: Bertil B
authors.initials: BB
authors.lastname: Fredholm
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Osamu
authors.initials: O
authors.lastname: Hayaishi
mesh_terms: D000241:Adenosine / Q000008:administration & dosage*; D058907:Adenosine A1 Receptor Agonists; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D003070:Coformycin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D007026:Hypothalamic Area, Lateral / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D011969:Receptors, Histamine H1 / Q000502:physiology*; D012894:Sleep Stages / Q000187:drug effects* / Q000502:physiology
chemical_list: D058907:Adenosine A1 Receptor Agonists; D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D043682:Receptor, Adenosine A1; D011969:Receptors, Histamine H1; D003070:Coformycin; D006632:Histamine; D000241:Adenosine