title: GABAB agonism promotes sleep and reduces cataplexy in murine narcolepsy.
abstract: γ-Hydroxybutyrate (GHB) is an approved therapeutic for the excessive sleepiness and sudden loss of muscle tone (cataplexy) characteristic of narcolepsy. The mechanism of action for these therapeutic effects is hypothesized to be GABAB receptor dependent. We evaluated the effects of chronic administration of GHB and the GABAB agonist R-baclofen (R-BAC) on arousal state and cataplexy in two models of narcolepsy: orexin/ataxin-3 (Atax) and orexin/tTA; TetO diphtheria toxin mice (DTA). Mice were implanted for EEG/EMG monitoring and dosed with GHB (150 mg/kg), R-BAC (2.8 mg/kg), or vehicle (VEH) bid for 15 d-a treatment paradigm designed to model the twice nightly GHB dosing regimen used by human narcoleptics. In both models, R-BAC increased NREM sleep time, intensity, and consolidation during the light period; wake bout duration increased and cataplexy decreased during the subsequent dark period. GHB did not increase NREM sleep consolidation or duration, although NREM delta power increased in the first hour after dosing. Cataplexy decreased from baseline in 57 and 86% of mice after GHB and R-BAC, respectively, whereas cataplexy increased in 79% of the mice after VEH. At the doses tested, R-BAC suppressed cataplexy to a greater extent than GHB. These results suggest utility of R-BAC-based therapeutics for narcolepsy.
authors.affiliation: Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California 94025 and Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
authors.forename: Sarah Wurts
authors.initials: SW
authors.lastname: Black
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Morairty
authors.forename: Tsui-Ming
authors.initials: TM
authors.lastname: Chen
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Leung
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Wisor
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamanaka
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kilduff
mesh_terms: D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology; D000067699:Ataxin-3; D002385:Cataplexy / Q000188:drug therapy*; D003627:Data Interpretation, Statistical; D004167:Diphtheria Toxin / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D018755:GABA Agonists / Q000627:therapeutic use*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009290:Narcolepsy / Q000188:drug therapy*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D000068797:Orexins; D018080:Receptors, GABA-B / Q000187:drug effects*; D012097:Repressor Proteins / Q000235:genetics; D012890:Sleep / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects; D012978:Sodium Oxybate / Q000627:therapeutic use*
chemical_list: D004167:Diphtheria Toxin; D018755:GABA Agonists; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D000068797:Orexins; D018080:Receptors, GABA-B; D012097:Repressor Proteins; D012978:Sodium Oxybate; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: GABA; cataplexy; hypocretin; narcolepsy; orexin; therapeutics