State-dependent alterations in sleep/wake architecture elicited by the M4 PAM XXXX - Relation to antipsychotic-like drug effects.

@entity1088 @entity3264 @entity3391 @entity1887 @entity71673 @entity161 @entity11755 @entity35 @entity3390 @entity15245 @entity25 @entity934
UNASSIGNED: Accumulating evidence indicates direct relationships between @entity25 and the severity and prevalence of other symptom clusters in @entity161 . Assessment of potential state-dependent alterations in @entity25 and arousal relative to antipsychotic-like activity is critical for the development of novel antipsychotic drugs (APDs). Recently, we reported that @entity71673 , a selective positive allosteric modulator (PAM) of the M4 muscarinic @entity934 receptor (mAChR), exhibits robust APD-like and cognitive enhancing activity in rodents. However, the state-dependent effects of @entity71673 on @entity25 and arousal have not been examined. Using polysomnography and quantitative electroencephalographic recordings from subcranial electrodes in @entity35 , we evaluated the effects of @entity71673 , in comparison with the atypical APD @entity1088 and the M1/M4-preferring mAChR agonist @entity15245 . @entity71673 induced state-dependent alterations in @entity25 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. @entity1088 decreased arousal during wake, increased cumulative NREM, and @entity11755 . In contrast, xanomeline increased time awake and arousal during wake, but reduced slow wave activity during NREM sleep. Additionally, in combination with the @entity3391 subtype of @entity3264 receptor (NMDAR) antagonist @entity3390 , modeling @entity1887 thought to underlie many symptoms in @entity161 , both @entity71673 and @entity1088 attenuated @entity3390 -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 @entity161 , including disruptions in @entity25 without a sedative profile.
