title: Reducing falls in Parkinson's disease: interactions between donepezil and the 5-HT6receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements.
abstract: Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson's disease (PD), the leading levodopa-insensitive cause of hospitalization and long-term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic-dopaminergic losses ("DL rats") and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT6receptor antagonist idalopirdine (Lu AE58054) was reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer's disease, here we assessed the effects of this treatment on MCMCT performance and attention in DL rats. Compared with the vehicle-treated group, the combined treatment greatly reduced (Cohen's d = 0.96) falls in DL rats when traversing dynamic surfaces and when exposed to a passive distractor. However, falls associated with a dual task distractor and sustained attentional performance did not benefit from this treatment. Analyses of the behavior in fall-prone moments suggested that this treatment improved the efficacy and speed of re-instating forward movement after relatively short stoppages. This treatment may reduce fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait.
authors.affiliation: Department of Psychology, University of Michigan, 530 Church Street, Ann Arbor, MI, 48109, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Kucinski
authors.affiliation: Division of Neurodegeneration, H. Lundbeck A/S, Valby, Denmark.
authors.forename: Inge E M
authors.initials: IE
authors.lastname: de Jong
authors.affiliation: Department of Psychology, University of Michigan, 530 Church Street, Ann Arbor, MI, 48109, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Sarter
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000188:drug therapy; D003342:Corpus Striatum / Q000187:drug effects; D000077265:Donepezil; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005684:Gait / Q000187:drug effects; D007189:Indans / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy*; D010880:Piperidines / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D005466:Fluorocarbons
chemical_list: D001596:Benzylamines; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D004298:Dopamine; D007189:Indans; D007211:Indoles; D010880:Piperidines; D011985:Receptors, Serotonin; C568612:(2-(6-fluoro-1H-indol-3-yl)-ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)amine; D005466:Fluorocarbons; C097216:serotonin 6 receptor
keywords: Parkinson's disease; attention; donepezil; falls; idalopirdine; rat