title: Role of adenosine and the orexinergic perifornical hypothalamus in sleep-promoting effects of ethanol.
abstract: OBJECTIVE
  Strong clinical and preclinical evidence suggests that acute ethanol promotes sleep. However, very little is known about how and where ethanol acts to promote sleep. We hypothesized that ethanol may induce sleep by increasing extracellular levels of adenosine and inhibiting orexin neurons in the perifornical hypothalamus.
  
  
  METHODS
  Experiments 1 and 2: Within-Subject Design; Experiment 3: Between-Subject Design.
  
  
  METHODS
  N/A.
  
  
  METHODS
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  METHODS
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  RESULTS
  Using adult male Sprague-Dawley rats as our animal model, we performed three experiments to test our hypothesis. Our first experiment examined the effect of A1 receptor blockade in the orexinergic perifornical hypothalamus on sleep- promoting effects of ethanol. Bilateral microinjection of the selective A1 receptor antagonist 1,3-dipropyl-8-phenylxanthine (500 μM; 250 nL/side) into orexinergic perifornical hypothalamus significantly reduced nonrapid eye movement sleep with a concomitant increase in wakefulness, suggesting that blockade of adenosine A1 receptor attenuates ethanol-induced sleep promotion. Our second experiment examined adenosine release in the orexinergic perifornical hypothalamus during local ethanol infusion. Local infusion of pharmacologically relevant doses of ethanol significantly and dose-dependently increased adenosine release. Our final experiment used c-Fos immunohistochemistry to examine the effects of ethanol on the activation of orexin neurons. Acute ethanol exposure significantly reduced the number of orexin neurons containing c-Fos, suggesting an inhibition of orexin neurons after ethanol intake.
  
  
  CONCLUSIONS
  Based on our results, we believe that ethanol promotes sleep by increasing adenosine in the orexinergic perifornical hypothalamus, resulting in A1 receptor-mediated inhibition of orexin neurons.
authors.affiliation: Harry S. Truman Memorial Veterans' Hospital and Department of Neurology, University of Missouri, Columbia, MO.
authors.forename: Rishi
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Harry S. Truman Memorial Veterans' Hospital and Department of Neurology, University of Missouri, Columbia, MO.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Sahota
authors.affiliation: Harry S. Truman Memorial Veterans' Hospital and Department of Neurology, University of Missouri, Columbia, MO.
authors.forename: Mahesh M
authors.initials: MM
authors.lastname: Thakkar
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000431:Ethanol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D012890:Sleep / Q000187:drug effects* / Q000502:physiology*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology; D014970:Xanthines / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D043682:Receptor, Adenosine A1; D014970:Xanthines; D000431:Ethanol; C049140:1,3-dipropyl-8-phenylxanthine; D000241:Adenosine
keywords: Adenosine; ethanol; microdialysis; orexin; sleep