title: Translational neurophysiological markers for activity of the metabotropic glutamate receptor (mGluR2) modulator JNJ-40411813: Sleep EEG correlates in rodents and healthy men.
abstract: Alterations in rapid eye movement sleep (REM) have been suggested as valid translational efficacy markers: activation of the metabotropic glutamate receptor 2 (mGluR2) was shown to increase REM latency and to decrease REM duration. The present paper addresses the effects on vigilance states of the mGluR2 positive allosteric modulator (PAM) JNJ-40411813 at different circadian times in rats and after afternoon dosing in humans. Due to its dual mGluR2 PAM/serotonin 2A (5-HT2A) receptor antagonism in rodents, mGlu2R specificity of effects was studied in wild-type (WT) and mGluR2 (-/-) mice. 5-HT2A receptor occupancy was determined in humans using positron emission tomography (PET). Tolerance development was examined in rats after chronic dosing. EEG oscillations and network connectivity were assessed using multi-channel EEG. In rats, JNJ-40411813 increased deep sleep time and latency of REM onset but reduced REM time when administered 2 h after 'lights on' (CT2): this was sustained after chronic dosing. At CT5 similar effects were elicited, at CT10 only deep sleep was enhanced. Withdrawal resulted in baseline values, while re-administration reinstated drug effects. Parieto-occipital cortical slow theta and gamma oscillations were correlated with low locomotion. The specificity of functional response was confirmed in WT but not mGluR2 (-/-) mice. A double-blind, placebo-controlled polysomnographic study in healthy, elderly subjects showed that 500 mg of JNJ-40411813 consistently increased deep sleep time, but had no effect on REM parameters. This deep sleep effect was not explained by 5-HT2A receptor binding, as in the PET study even 700 mg only marginally displaced the tracer. JNJ-40411813 elicited comparable functional responses in rodents and men if circadian time of dosing was taken into account. These findings underscore the translational potential of sleep mechanisms in evaluating mGluR2 therapeutics when administered at the appropriate circadian time.
authors.affiliation: Dept. of Neuroscience Discovery, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium. Electronic address: aahnaou@its.jnj.com.
authors.forename: A
authors.initials: A
authors.lastname: Ahnaou
authors.affiliation: Neuroscience Experimental Medicine, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: de Boer
authors.affiliation: Dept. of Neuroscience Discovery, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Lavreysen
authors.affiliation: Dept. of Neuroscience Discovery, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Huysmans
authors.affiliation: Clinical Pharmacology in Titusville, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560 USA.
authors.forename: V
authors.initials: V
authors.lastname: Sinha
authors.affiliation: Dept. of Neuroscience Discovery, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Raeymaekers
authors.affiliation: Nonclinical Statistics and Computing, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: T
authors.initials: T
authors.lastname: Van De Casteele
authors.affiliation: Neuroscience Discovery, Toledo C/Jarama, 75, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Cid
authors.affiliation: Neuroscience Experimental Medicine, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Van Nueten
authors.affiliation: Dept. of Neuroscience Discovery, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: G J
authors.initials: GJ
authors.lastname: Macdonald
authors.affiliation: Dept. of Neuroscience Discovery, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: J A
authors.initials: JA
authors.lastname: Kemp
authors.affiliation: Dept. of Neuroscience Discovery, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: W H I M
authors.initials: WH
authors.lastname: Drinkenburg
mesh_terms: D000328:Adult; D000494:Allosteric Regulation; D000818:Animals; D058256:Brain Waves / Q000187:drug effects; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology*; D002940:Circadian Rhythm / Q000187:drug effects*; D004569:Electroencephalography; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage* / Q000097:blood* / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011728:Pyridones / Q000008:administration & dosage* / Q000097:blood* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000008:administration & dosage; D012890:Sleep / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects; D057170:Translational Research, Biomedical; D055815:Young Adult
chemical_list: C000594993:1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone; D010880:Piperidines; D011728:Pyridones; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; D058830:Serotonin 5-HT2 Receptor Antagonists; C108822:metabotropic glutamate receptor 2
keywords: Circadian; Glutamate; Men; Metabotropic receptor mGluR2; Network oscillations and connectivity; Polysomnography; Positron Emission Tomography (PET); Psychiatric disorders; Rat; Sleep-wake cycle; Tolerance; Translational; mGluR2 (−/−) mice