Effects of the M4 muscarinic receptor positive allosteric modulator VU0467154 on cognition and pyramidal cell firing properties in layer V of the mPFC (845.9)

Many symptoms in schizophrenia are attributed to alternations in normal glutamatergic signaling in the prefrontal cortex (PFC). In preclinical studies, psychotomimetic agents like the N-methyl-D-aspartate receptor antagonist MK-801 induce enhanced spontaneous firing at glutamatergic synapses within the medial PFC and cognitive impairments. Recently, we reported the discovery of VU0467154, an optimized positive allosteric modulator (PAMs) of the M4 muscarinic acetylcholine receptor with low nanomolar potency in vitro and suitable pharmacokinetic properties for in vivo studies. Here we evaluated the ability of VU0467154 to reverse alterations in mPFC signaling and behavioral deficits induced by MK-801. In vivo electrophysiology studies in anesthetized rats revealed that pretreatment with VU0467154 reversed MK-801-induced changes in firing rates in layer V pyramidal cells of the mPFC, while having no effect on firing rates when administered alone. Moreover, VU0467154 produced dose-related reversals of MK-801...