Broad Cognitive and Motivational Enhancement through M4-Selective Muscarinic Modulation

In nonhuman primates, an M4-selective positive allosteric modulator improves multiple executive and attention measures dose-dependently, while reducing effort avoidance in an effort-based choice task.

• Why it matters: M4-subtype selective modulation is promising for Schizophrenia and Alzheimer’s disease, but its effects on cognition and motivation are unclear due to dose-limiting side effects and limited receptor-selective tools.
• What they did: The study used an M4-selective PAM in nonhuman primates, testing multi-domain cognitive endpoints plus an effort-based choice task, and also computed task-composite performance scores.
• The result: Performance improved across set shifting, visual search, antisaccades, visuospatial maze learning, and temporal order serial object learning, with working memory span non-systematically modulated and pro-motivational effects without adverse dose-limiting cholinergic side effects.

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