title: The mouse beam walking assay offers improved sensitivity over the mouse rotarod in determining motor coordination deficits induced by benzodiazepines.
abstract: The mouse rotarod test of motor coordination/sedation is commonly used to predict clinical sedation caused by novel drugs. However, past experience suggests that it lacks the desired degree of sensitivity to be predictive of effects in humans. For example, the benzodiazepine, bretazenil, showed little impairment of mouse rotarod performance, but marked sedation in humans. The aim of the present study was to assess whether the mouse beam walking assay demonstrates: (i) an increased sensitivity over the rotarod and (ii) an increased ability to predict clinically sedative doses of benzodiazepines. The study compared the effects of the full benzodiazepine agonists, diazepam and lorazepam, and the partial agonist, bretazenil, on the mouse rotarod and beam walking assays. Diazepam and lorazepam significantly impaired rotarod performance, although relatively high GABA-A receptor occupancy was required (72% and 93%, respectively), whereas beam walking performance was significantly affected at approximately 30% receptor occupancy. Bretazenil produced significant deficits at 90% and 53% receptor occupancy on the rotarod and beam walking assays, respectively. The results suggest that the mouse beam walking assay is a more sensitive tool for determining benzodiazepine-induced motor coordination deficits than the rotarod. Furthermore, the GABA-A receptor occupancy values at which significant deficits were determined in the beam walking assay are comparable with those observed in clinical positron emission tomography studies using sedative doses of benzodiazepines. These data suggest that the beam walking assay may be able to more accurately predict the clinically sedative doses of novel benzodiazepine-like drugs.
authors.affiliation: Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, UK. jo_stanley@merck.com
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Stanley
authors.forename: Rachael J
authors.initials: RJ
authors.lastname: Lincoln
authors.forename: Terry A
authors.initials: TA
authors.lastname: Brown
authors.forename: Louise M
authors.initials: LM
authors.lastname: McDonald
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.forename: David S
authors.initials: DS
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects*; D008140:Lorazepam / Q000494:pharmacology; D008297:Male; D051379:Mice; D004856:Postural Balance / Q000187:drug effects*; D011237:Predictive Value of Tests
chemical_list: D001570:Benzodiazepinones; D002492:Central Nervous System Depressants; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D001569:Benzodiazepines; D000431:Ethanol; D008140:Lorazepam; C054626:bretazenil; D003975:Diazepam