title: Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy.
abstract: OBJECTIVE
  Humans with narcolepsy and orexin/ataxin-3 transgenic (TG) mice exhibit extensive, but incomplete, degeneration of hypo-cretin (Hcrt) neurons. Partial Hcrt cell loss also occurs in Parkinson disease and other neurologic conditions. Whether Hcrt antagonists such as almorexant (ALM) can exert an effect on the Hcrt that remains after Hcrt neurodegeneration has not yet been determined. The current study was designed to evaluate the hypnotic and cataplexy-inducing efficacy of a Hcrt antagonist in an animal model with low Hcrt tone and compare the ALM efficacy profile in the disease model to that produced in wild-type (WT) control animals.
  
  
  METHODS
  Counterbalanced crossover study.
  
  
  METHODS
  Home cage.
  
  
  METHODS
  Nine TG mice and 10 WT mice.
  
  
  METHODS
  ALM (30, 100, 300 mg/kg), vehicle and positive control injections, dark/active phase onset.
  
  
  RESULTS
  During the 12-h dark period after dosing, ALM exacerbated cataplexy in TG mice and increased nonrapid eye movement sleep with heightened sleep/wake fragmentation in both genotypes. ALM showed greater hypnotic potency in WT mice than in TG mice. The 100 mg/kg dose conferred maximal promotion of cataplexy in TG mice and maximal promotion of REM sleep in WT mice. In TG mice, ALM (30 mg/ kg) paradoxically induced a transient increase in active wakefulness. Core body temperature (Tb) decreased after acute Hcrt receptor blockade, but the reduction in Tb that normally accompanies the wake-to-sleep transition was blunted in TG mice.
  
  
  CONCLUSIONS
  These complex dose- and genotype-dependent interactions underscore the importance of effector mechanisms downstream from Hcrt receptors that regulate arousal state. Cataplexy promotion by ALM warrants cautious use of Hcrt antagonists in patient populations with Hcrt neurodegeneration, but may also facilitate the discovery of anticataplectic medications.
  
  
  BACKGROUND
  Black SW; Morairty SR; Fisher SP; Chen TM; Warrier DR; Kilduff TS. Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. SLEEP 2013;36(3):325-336.
authors: Biosciences Division, SRI International, Menlo Park, CA 94025, USA. sarah.black@sri.com
authors: Sarah Wurts
authors: SW
authors: Black
authors: Stephen R
authors: SR
authors: Morairty
authors: Simon P
authors: SP
authors: Fisher
authors: Tsui-Ming
authors: TM
authors: Chen
authors: Deepti R
authors: DR
authors: Warrier
authors: Thomas S
authors: TS
authors: Kilduff
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002385:Cataplexy / Q000139:chemically induced*; D018592:Cross-Over Studies; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009290:Narcolepsy / Q000188:drug therapy*; D009474:Neurons / Q000187:drug effects; D009479:Neuropeptides / Q000187:drug effects; D000068797:Orexins; D012890:Sleep / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects
chemical_list: D000081:Acetamides; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D009479:Neuropeptides; D000068797:Orexins; C519150:almorexant
keywords: Cataplexy; hypocretin; mouse; narcolepsy; orexin