Selective M4 Positive Allosteric Modulator VU6008055 Enhances Higher Executive Functions in the Nonhuman Primate: A Multitask Assessment

This abstract is for Neuroscience 2026, held November 14–18 in Washington, D.C.

Abstract

Muscarinic cholinergic receptors have been implicated in some of the pro-cognitive effects of cholinergic drugs, but the specific contributions of the M4 muscarinic receptor subtype have remained unclear in higher-order species. We addressed this question using VU6008055, a highly selective and potent M4 positive allosteric modulator (PAM) intended to avoid common cholinergic side effects, and a multitask assessment battery for nonhuman primates (NHPs). The battery assessed multiple executive functions in the same subjects and pharmacological paradigm, with tasks designed to align with human diagnostic test batteries for schizophrenia.

Six healthy adult rhesus macaques received three doses of VU6008055 and vehicle across seven determinations over 28 weeks. After dose administration, subjects completed experimental sessions lasting approximately 80 minutes. Each session included four tasks drawn from a seven-task battery, including visual search (attention), set shifting (cognitive flexibility), working memory updating, antisaccade (cognitive control), object-sequence learning (visual planning), and hidden maze learning (visuospatial skills). The tasks were performed at touchscreen stations mounted to the home cages of pair-housed NHPs.

Dose-specific improvements were observed across subjects in attention, cognitive flexibility, inhibitory control, visuospatial skills, and visual planning. No adverse side effects were noted across the tested dose range. Compared with vehicle, subjects’ best doses produced improvements across cognitive domains, while effects at their worst doses were few and nonsystematic. Improvements were more prevalent in challenging task conditions.

These findings support a role for the M4 muscarinic receptor in higher-order, domain-general cognitive functions in NHPs. The broad pro-cognitive effects support further study of M4 PAMs as potential treatments for cognitive symptoms in psychiatric disorders.