The Effects of the M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0486846 on Cognitive Performance in Aged Nonhuman Primates

Abstract

It is estimated that in the United States alone there will be nearly 70 million people over the age of 65 by the year 2030. Yet, there remains a critical unmet need to understand and identify novel therapeutic strategies to address age‐related impairments in arousal, cognitive function, and sleep architecture. Agents such as acetylcholinesterase inhibitors (AChEIs) that enhance overall cholinergic neurotransmission are approved to ameliorate the loss of cognitive function in normal aging and Alzheimer’s disease (AD) populations. However, AChEIs are associated with dose‐limiting side effect due to nonselective activation of peripheral muscarinic acetylcholine receptors (mAChRs). Accumulating evidence indicates that enhancement of central cholinergic neurotransmission through selective activation of the M1 mAChR subtype represents an exciting alternative approach for the treatment of impairments in cognition, arousal and sleep observed in normal aging and AD. Recently we successfully optimized a novel series of M1 positive allosteric modulators (PAMs) as an alternative strategy for the selective activation of M1 receptors, represented by VU0486846. The goal of the present study was to provide the first characterization of the effects of an M1 PAM on cognitive performance in aged nonhuman primates. For these studies, 16 aged (> 20 years old) female and male (N=8/sex) cynomolgus monkeys were trained under two different cognitive tasks using CANTAB touchscreens. Eight monkeys (N=4/sex) were trained under a delayed match‐to‐sample (DMS) task using three delays and 2–3 distractors. The other monkeys were trained under an attention task, the multiple‐choice serial reaction time (MCSRT) task. All monkeys were tested with the following compounds, administered 60‐min before the session: donepezil (0.1–0.56 mg/kg, IM); VU0486846 (1.0–5.6 mg/kg, PO) and d‐amphetamine (0.01–0.056 mg/kg, IM). With no published data on training of aged monkeys in a DMS task, we found that the eight aged monkeys required approximately 1 year of training prior to pharmacologic challenge. The effects of donepezil were variable across monkeys, up to doses that produced adverse effects. In contrast, VU0486846 improved working memory, at doses that did not result in any side effects. As a positive control, d‐amphetamine also improved cognitive performance. In preliminary studies, testing ineffective doses of donepezil + VU0486846 also resulted in improved DMS performance. Regarding MCSRT, effects of both donepezil and VU0486846 were determined on a reaction time task. At doses that improved working memory, VU0486846 did not affect reaction time while in some but not all monkeys, donepezil slowed reaction times. These promising preliminary data will be extended in order to examine sex‐specific and age‐related effects of chronic VU0486846 and the consequences of the M1 PAM and donepezil on sleep architecture in aged nonhuman primates.Support or Funding InformationNIH grant AG054622