Hypocretin and GABA interact in the pontine reticular formation to increase wakefulness.
OBJECTIVE
Hypocretin-1/orexin A administered directly into the oral part of rat pontine reticular formation (PnO) causes an increase in wakefulness and extracellular gamma-aminobutyric acid (GABA) levels. The receptors in the PnO that mediate these effects have not been identified. Therefore, this study tested the hypothesis that the increase in wakefulness caused by administration of hypocretin-1 into the PnO occurs via activation of GABAA receptors and hypocretin receptors.


METHODS
Within/between subjects.


METHODS
University of Michigan.


METHODS
Twenty-three adult male Crl:CD*(SD) (Sprague Dawley) rats.


METHODS
Microinjection of hypocretin-1, bicuculline (GABAA receptor antagonist), SB-334867 (hypocretin receptor-1 antagonist), and Ringer solution (vehicle control) into the PnO.


RESULTS
Hypocretin-1 caused a significant concentration-dependent increase in wakefulness and decrease in rapid eye movement (REM) sleep and non-REM (NREM) sleep. Coadministration of SB-334867 and hypocretin-1 blocked the hypocretin-1-induced increase in wakefulness and decrease in both the NREM and REM phases of sleep. Coadministration of bicuculline and hypocretin-1 blocked the hypocretin-1-induced increase in wakefulness and decrease in NREM sleep caused by hypocretin-1.


CONCLUSIONS
The increase in wakefulness caused by administering hypocretin-1 to the PnO is mediated by hypocretin receptors and GABAA receptors in the PnO. These results show for the first time that hypocretinergic and GABAergic transmission in the PnO can interact to promote wakefulness.
Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109-5615, USA.
Holly N
HN
Brevig
Christopher J
CJ
Watson
Ralph
R
Lydic
Helen A
HA
Baghdoyan
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001583:Benzoxazoles / Q000378:metabolism / Q000493:pharmacokinetics; D001640:Bicuculline / Q000378:metabolism / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology*; D007552:Isotonic Solutions / Q000008:administration & dosage; D008297:Male; D008845:Microinjections; D009287:Naphthyridines; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology*; D000068797:Orexins; D011149:Pons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012154:Reticular Formation / Q000187:drug effects / Q000378:metabolism*; D000077331:Ringer's Solution; D012894:Sleep Stages / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000187:drug effects* / Q000378:metabolism*
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D058785:GABA-A Receptor Agonists; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D007552:Isotonic Solutions; D009287:Naphthyridines; D009479:Neuropeptides; D000068797:Orexins; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D000077331:Ringer's Solution; D014508:Urea; D001640:Bicuculline