title: Distinctive recruitment of endogenous sleep-promoting neurons by volatile anesthetics and a nonimmobilizer.
abstract: BACKGROUND
  Numerous studies demonstrate that anesthetic-induced unconsciousness is accompanied by activation of hypothalamic sleep-promoting neurons, which occurs through both pre- and postsynaptic mechanisms. However, the correlation between drug exposure, neuronal activation, and onset of hypnosis remains incompletely understood. Moreover, the degree to which anesthetics activate both endogenous populations of γ-aminobutyric acid (GABA)ergic sleep-promoting neurons within the ventrolateral preoptic (VLPO) and median preoptic nuclei remains unknown.
  
  
  METHODS
  Mice were exposed to oxygen, hypnotic doses of isoflurane or halothane, or 1,2-dichlorohexafluorocyclobutane (F6), a nonimmobilizer. Hypothalamic brain slices prepared from anesthetic-naive mice were also exposed to oxygen, volatile anesthetics, or F6 ex vivo, both in the presence and absence of tetrodotoxin. Double-label immunohistochemistry was performed to quantify the number of c-Fos-immunoreactive nuclei in the GABAergic subpopulation of neurons in the VLPO and the median preoptic areas to test the hypothesis that volatile anesthetics, but not nonimmobilizers, activate sleep-promoting neurons in both nuclei.
  
  
  RESULTS
  In vivo exposure to isoflurane and halothane doubled the fraction of active, c-Fos-expressing GABAergic neurons in the VLPO, whereas F6 failed to affect VLPO c-Fos expression. Both in the presence and absence of tetrodotoxin, isoflurane dose-dependently increased c-Fos expression in GABAergic neurons ex vivo, whereas F6 failed to alter expression. In GABAergic neurons of the median preoptic area, c-Fos expression increased with isoflurane and F6, but not with halothane exposure.
  
  
  CONCLUSIONS
  Anesthetic unconsciousness is not accompanied by global activation of all putative sleep-promoting neurons. However, within the VLPO hypnotic doses of volatile anesthetics, but not nonimmobilizers, activate putative sleep-promoting neurons, correlating with the appearance of the hypnotic state.
authors: From the Department of Anesthesiology and Critical Care (B.H.), Department of Pharmacology (H.S.M.), University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania; Department of Anesthesiology, Weill Cornell Medical College, New York, New York (D.O.); and Department of Anesthesiology and Critical Care, Center for Sleep and Circadian Neurobiology, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania (M.B.K.).
authors: Bo
authors: B
authors: Han
authors: Hilary S
authors: HS
authors: McCarren
authors: Dan
authors: D
authors: O'Neill
authors: Max B
authors: MB
authors: Kelz
mesh_terms: D000777:Anesthetics / Q000494:pharmacology*; D000818:Animals; D017402:Chlorofluorocarbons / Q000494:pharmacology*; D003503:Cyclobutanes / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D011301:Preoptic Area / Q000166:cytology / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011999:Recruitment, Neurophysiological / Q000187:drug effects*; D012890:Sleep / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D000777:Anesthetics; D017402:Chlorofluorocarbons; D003503:Cyclobutanes; D016760:Proto-Oncogene Proteins c-fos; C090640:1,2-dichloro-1,2,3,3,4,4-hexafluorocyclobutane; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase