title: A single dose of hypnotic corrects sleep and EEG abnormalities in symptomatic Huntington's disease mice.
abstract: Sleep and electroencephalogram abnormalities are prominent early features of Huntington's disease (HD) that typically appear before the onset of characteristic motor symptoms. The changes in sleep and electroencephalogram seen in HD patients are largely recapitulated in mouse models of HD such as transgenic R6/2 lines. To test whether or not drugs with hypnotic properties can correct the sleep and electroencephalogram abnormalities seen in HD mice, we treated male wild-type (WT; N = 7) and R6/2 mice (N = 9) acutely with intraperitoneal injections of vehicle, zolpidem (5, 10 or 20 mg/kg) or amitriptyline (5, 10 or 20 mg/kg), and then monitored their sleep-wake behavior. In R6/2 mice, both zolpidem and amitriptyline suppressed the abnormally high REM sleep amount and electroencephalographic gamma (30-46 Hz) oscillations in a dose-dependent manner. Amitriptyline's effect on sleep was similar in both genotypes, whereas zolpidem showed significant genotype differences. Zolpidem exerted a strong hypnotic effect in WT mice by increasing electroencephalographic delta power, doubling the mean bout duration and the total amount of non-rapid eye movement sleep. However, no such effect was seen in R6/2 mice. Our study demonstrates that the pathophysiological changes seen in sleep and electroencephalogram are not 'hard-wired' in HD brain and can be reversed even at late stages of the disease. The diminished hypnotic effect of zolpidem suggests that the GABAergic control of sleep-wake states is impaired in HD mice. A better understanding of the neurochemical basis underlying these abnormalities should lead to more effective and rational therapies for HD.
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
authors.forename: Sandor
authors.initials: S
authors.lastname: Kantor
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
authors.forename: Janos
authors.initials: J
authors.lastname: Varga
authors.affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom. Electronic address: ajm41@cam.ac.uk.
authors.forename: A Jennifer
authors.initials: AJ
authors.lastname: Morton
mesh_terms: D000639:Amitriptyline / Q000627:therapeutic use; D000818:Animals; D001143:Arousal / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects*; D006816:Huntington Disease / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics; D006993:Hypnotics and Sedatives / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017286:Polysomnography; D011725:Pyridines / Q000627:therapeutic use; D012890:Sleep / Q000187:drug effects; D012893:Sleep Wake Disorders / Q000188:drug therapy* / Q000209:etiology*; D012895:Sleep, REM / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects; D000077334:Zolpidem
chemical_list: D006993:Hypnotics and Sedatives; D011725:Pyridines; D000639:Amitriptyline; D000077334:Zolpidem
keywords: Antidepressants; Gamma oscillation; Hypnotic drugs; Quantitative EEG; REM sleep; Transgenic mice