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.