GABA_B 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 GABA B receptor dependent. We evaluated the effects of chronic administration of GHB and the GABA B 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.

Keywords: cataplexy; GABA; hypocretin; narcolepsy; orexin; therapeutics