title: Effects of the 5-HT6receptor antagonist idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the rat medial prefrontal cortex.
abstract: Idalopirdine (Lu AE58054) is a high affinity and selective antagonist for the human serotonin 5-HT6receptor (Ki0.83nM) in phase III development for mild-to-moderate Alzheimer's disease as an adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We have studied the effects of idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the medial prefrontal cortex (mPFC) of freely-moving rats using microdialysis. Idalopirdine (10mg/kg p.o.) increased extracellular levels of dopamine, noradrenaline and glutamate in the mPFC and showed a trend to increase serotonin levels. No effect was observed on acetylcholine levels. The AChEI donepezil (1.3mg/kg s.c.) significantly increased the levels of acetylcholine. Pretreatment with idalopirdine 2h prior to donepezil administration potentiated the effect of donepezil on extracellular acetylcholine levels. The idalopirdine potentiation of donepezil-induced increase in acetylcholine levels was also observed during local infusion of idalopirdine (6µg/ml) into the mPFC by reverse dialysis. The data from the current study may provide a mechanistic model for the pro-cognitive effects observed with administration of idalopirdine in donepezil-treated patients with Alzheimer's disease observed in the phase 2 studies (Wilkinson et al. 2014).
authors.affiliation: Synaptic Transmission In Vivo, 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: Synaptic Transmission In Vivo, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Rasmus Vinther
authors.initials: RV
authors.lastname: Russell
authors.affiliation: Division of Neurodegeneration, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Inge E M
authors.initials: IE
authors.lastname: de Jong
authors.affiliation: Lundbeck Research, 215 College Rd., Paramus, USA.
authors.forename: Gennady
authors.initials: G
authors.lastname: Smagin
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D017397:Prefrontal Cortex / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D005466:Fluorocarbons
chemical_list: D000109:Acetylcholine; D001596:Benzylamines; D015306:Biogenic Monoamines; D018698:Glutamic Acid; 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: Alzheimer's disease; Donepezil; Idalopirdine; Serotonin 5-HT(6) receptor