title: The 5-HT6receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleep-wake architecture.
abstract: The 5-HT6receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD). The high affinity and selective 5-HT6receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on cortical function using two in vivo electrophysiological methods. Neuronal network oscillations in the frontal cortex were measured during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and by an electroencephalogram (EEG) in the awake, freely moving rat. In conjunction with the EEG study, we investigated the effects of idalopirdine and donepezil on sleep-wake architecture using telemetric polysomnography. Idalopirdine (2 mg/kg i.v.) increased gamma power in the medial prefrontal cortex (mPFC) during nPO stimulation. Donepezil (0.3 and 1 mg/kg i.v.) also increased cortical gamma power and pretreatment with idalopirdine (2 mg/kg i.v.) potentiated and prolonged the effects of donepezil. Similarly, donepezil (1 and 3 mg/kg s.c.) dose-dependently increased frontal cortical gamma power in the freely moving rat and pretreatment with idalopirdine (10 mg/kg p.o.) augmented the effect of donepezil 1 mg/kg. Analysis of the sleep-wake architecture showed that donepezil (1 and 3 mg/kg s.c.) dose-dependently delayed sleep onset and decreased the time spent in both REM and non REM sleep stages. In contrast, idalopirdine (10 mg/kg p.o.) did not affect sleep-wake architecture nor the effects of donepezil. In summary, we show that idalopirdine potentiates the effects of donepezil on frontal cortical gamma oscillations, a pharmacodynamic biomarker associated with cognition, without modifying the effects of donepezil on sleep. The increased cortical excitability may contribute to the procognitive effects of idalopirdine in donepezil-treated AD patients.
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: maaf@lundbeck.com.
authors.forename: Maria
authors.initials: M
authors.lastname: Amat-Foraster
authors.affiliation: Lundbeck Research USA, Inc., Paramus, NJ 07652, USA. Electronic address: stevenleiser@gmail.com.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Leiser
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: kfh@lundbeck.com.
authors.forename: Kjartan F
authors.initials: KF
authors.lastname: Herrik
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: nelly-richard@hotmail.com.
authors.forename: Nelly
authors.initials: N
authors.lastname: Richard
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: clsg@lundbeck.com.
authors.forename: Claus
authors.initials: C
authors.lastname: Agerskov
authors.affiliation: Discovery DMPK, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: cbun@lundbeck.com.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Division of Synaptic Transmission, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: jfb@lundbeck.com.
authors.forename: Jesper F
authors.initials: JF
authors.lastname: Bastlund
authors.affiliation: Division of Neurodegeneration, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: idj@lundbeck.com.
authors.forename: Inge E M
authors.initials: IEM
authors.lastname: de Jong
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage*; D001933:Brain Stem / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage*; D000077265:Donepezil; D004558:Electric Stimulation; D004569:Electroencephalography; D005625:Frontal Lobe / Q000187:drug effects / Q000502:physiology*; D065818:Gamma Rhythm / Q000187:drug effects*; D007189:Indans / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D010880:Piperidines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000008:administration & dosage*; D012894:Sleep Stages / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects; D005466:Fluorocarbons
chemical_list: D001596:Benzylamines; D002800:Cholinesterase Inhibitors; D000077265:Donepezil; D007189:Indans; D007211:Indoles; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C568612:(2-(6-fluoro-1H-indol-3-yl)-ethyl)-(3-(2,2,3,3-tetrafluoropropoxy)benzyl)amine; D005466:Fluorocarbons; C097216:serotonin 6 receptor
keywords: 5-HT(6) receptor; Acetylcholinesterase inhibitor; Alzheimer's disease; Chemical compounds studied in this article: Donepezil (PubChem CID 3152); EEG; Idalopirdine; Idalopirdine (PubChem CID 21071390); sleep