Broad Cognitive and Motivational Enhancement through M4-Selective Muscarinic Modulation

The muscarinic M4 subtype of acetylcholine receptors is part of agonist compounds considered treatment options for Schizophrenia and Alzheimers disease, but how M4-subtype selective modulation affects cognition and motivation is largely unknown due to dose-limiting side effects, a scarcity of receptor-selective compounds, and missing multi-domain assessments of cognition. Here, we surmount these constraints by utilizing a M4-selective positive allosteric modulator (PAM) to assess in nonhuman primates a broad array of endpoints spanning motivational effort control and multiple executive function domains. We found broad dose-dependent performance improvements of set shifting indexing cognitive flexibility, visual search indexing selective attention, antisaccade performance indexing inhibitory control, visuospatial maze learning, and temporal order serial object learning, while working memory span was non-systematically modulated. In addition, the M4 PAM reduced effort avoidance in an effort-based choice task documenting a pro-motivational effect. Task-composite performance scores showed pro-cognitive effects across multiple doses and an effective dose range for individual subjects in the absence of adverse dose-limiting cholinergic side effects. Together, the broad pro-cognitive and pro-motivational multi-task profile of M4 PAM modulation suggests that the M4 receptor is a master regulator of executive cognitive functioning, possibly acting on domain-general neural processes across the prefrontal-striatal circuits.