title: State-dependent alterations in sleep/wake architecture elicited by the M4 PAM VU0467154 - Relation to antipsychotic-like drug effects.
abstract: Accumulating evidence indicates direct relationships between sleep abnormalities and the severity and prevalence of other symptom clusters in schizophrenia. Assessment of potential state-dependent alterations in sleep architecture and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that VU0467154, a selective positive allosteric modulator (PAM) of the M4 muscarinic acetylcholine receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of VU0467154 on sleep architecture and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in rats, we evaluated the effects of VU0467154, in comparison with the atypical APD clozapine and the M1/M4-preferring mAChR agonist xanomeline. VU0467154 induced state-dependent alterations in sleep architecture and arousal including delayed Rapid Eye Movement (REM) sleep onset, increased cumulative duration of total and Non-Rapid Eye Movement (NREM) sleep, and increased arousal during waking periods. Clozapine decreased arousal during wake, increased cumulative NREM, and decreased REM sleep. In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the N-methyl-d-aspartate subtype of glutamate receptor (NMDAR) antagonist MK-801, modeling NMDAR hypofunction thought to underlie many symptoms in schizophrenia, both VU0467154 and clozapine attenuated MK-801-induced elevations in high frequency gamma power consistent with an APD-like mechanism of action. These findings suggest that selective M4 PAMs may represent a novel mechanism for treating multiple symptoms of schizophrenia, including disruptions in sleep architecture without a sedative profile.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gould
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Nedelcovych
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Gong
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Tsai
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bubser
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wood
authors.affiliation: Neuroscience Innovative Medicines, AstraZeneca, Cambridge, MA 02139, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Duggan
authors.affiliation: Neuroscience Innovative Medicines, AstraZeneca, Cambridge, MA 02139, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Brandon
authors.affiliation: Neuroscience Innovative Medicines, AstraZeneca, Cambridge, MA 02139, USA.
authors.forename: John
authors.initials: J
authors.lastname: Dunlop
authors.affiliation: Neuroscience Innovative Medicines, AstraZeneca, Cambridge, MA 02139, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Wood
authors.affiliation: Proteostasis Therapeutics, 200 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Magnus
authors.initials: M
authors.lastname: Ivarsson
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Noetzel
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: carrie.jones@vanderbilt.edu.
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001143:Arousal / Q000187:drug effects; D004569:Electroencephalography; D008297:Male; D017286:Polysomnography; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D043588:Receptor, Muscarinic M4 / Q000819:agonists*; D012890:Sleep / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C000599366:5-amino-3,4-dimethyl-N-(4-((trifluoromethyl)sulfonyl)benzyl)thieno(2,3-c)pyridazine-6-carboxamide; D011724:Pyridazines; D043588:Receptor, Muscarinic M4; D013876:Thiophenes
keywords: Clozapine; Electroencephalography; M(4) muscarinic acetylcholine receptor; Positive allosteric modulator; VU0467154; Xanomeline