title: The 5-HT6 receptor antagonist idalopirdine potentiates the effects of acetylcholinesterase inhibition on neuronal network oscillations and extracellular acetylcholine levels in the rat dorsal hippocampus.
abstract: The 5-HT6 receptor has emerged as a promising target for cognitive disorders and combining a 5-HT6 receptor antagonist with an acetylcholinesterase inhibitor (AChEI) represents a novel approach for the symptomatic treatment of Alzheimer's disease (AD). A recent phase 2 trial showed that the selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) improved cognition in patients with moderate AD on stable treatment with the AChEI donepezil. Here we investigated the effects of idalopirdine in combination with donepezil on hippocampal function using in vivo electrophysiology and microdialysis. Network oscillations in the hippocampus were recorded during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and hippocampal acetylcholine (ACh) levels were measured in the freely-moving rat. In addition, potential pharmacokinetic interactions between idalopirdine and donepezil were assessed. Idalopirdine alone did not affect hippocampal network oscillations or ACh levels. Donepezil (0.3 and 1.0 mg/kg i.v.) dose-dependently increased hippocampal theta and gamma power during nPO stimulation. Idalopirdine (2 mg/kg i.v.), administered 1 h prior to donepezil, potentiated the theta and gamma response to 0.3 mg/kg donepezil and prolonged the gamma response to 1 mg/kg donepezil. Donepezil (1.3 mg/kg s.c.) increased extracellular ACh levels in the hippocampus and this was further augmented by administration of idalopirdine (10 mg/kg p.o.) 2 h prior to donepezil. These effects could not be attributed to a pharmacokinetic interaction between the compounds. This study demonstrates that idalopirdine potentiates the effects of donepezil on two pharmacodynamic biomarkers associated with cognition, i.e. neuronal oscillations and extracellular ACh levels in the hippocampus. Such potentiation could contribute to the procognitive effects of idalopirdine observed in donepezil-treated AD patients.
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: arm@lundbeck.com.
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
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: 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: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage*; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology; D058256:Brain Waves / Q000187:drug effects / Q000502:physiology*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage*; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D005466:Fluorocarbons
chemical_list: D000109:Acetylcholine; D001596:Benzylamines; D002800:Cholinesterase Inhibitors; D007211:Indoles; 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; Acetylcholine; Alzheimer's disease; Donepezil; Donepezil (PubChem CID 3152); Idalopirdine; Idalopirdine (PubChem CID 21071390); Neuronal oscillations