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 by delaying Rapid Eye Movement (REM) sleep onset, selectively 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.

Disrupted Sleep and Circadian Rhythms in Schizophrenia and Their Interaction With Dopamine Signaling

“…This is likely due to their different pharmacological profiles; they each act on multiple neurotransmitter systems in addition to dopamine, including serotonin, noradrenaline, and histamine (Miyamoto et al, 2005). Rodent studies have shown that antipsychotic drugs with different receptor selectivity have differential effects on sleep/wake states (Ongini et al, 1993;Gould et al, 2016).…”

Phenotypic profiling of mGlu7 knockout mice reveals new implications for neurodevelopmental disorders

“…At 5 to 6 weeks of age, female Grm7 +/+ and Grm7 −/− mice were surgically implanted under isoflurane anesthesia with a telemetric transmitter (HD-X02; Data Sciences International [DSI], Minneapolis, MN) for recording EEG, electromyography (EMG) and motor activity as previously described. [18][19][20] Transmitters were implanted subcutaneously just off the midline of the dorsal flank of each mouse under aseptic conditions. Transmitter leads were tunneled subcutaneously to the skull.…”

Discovery of new GPCR ligands to illuminate new biology

“…Leveraging the PAM LY2033298, Conn and colleagues discovered a submicromolar PAM of acetylcholine, VU0152100, that was specific for the M4 receptor subtype 68 . Rounds of synthetic optimization led to PAMs that are more CNS penetrant and stable in vivo 69 and that have interesting new biology, including modulation of sleep– wake disturbances associated with schizophrenia. Meanwhile, a compound from Merck, MK-6884, is in phase I trials as a potential positron emission tomography (PET) ligand to assess occupancy of M4 PAMs in vivo (NCT02621606).…”