Dissociating the pro‐cognitive effects of donepezil and an M1 PAM

Abstract

AbstractBackgroundDonepezil, an FDA approved drug for dementia in Alzheimer’s disease, increases the extracellular concentration of acetylcholine non‐selectively stimulating cholinergic receptors indiscriminately leading to dose‐limiting side effects. Muscarinic M1 sub‐receptor specific positive allosteric modulators (PAMs) have shown promise in addressing symptoms in Alzheimer’s disease, Schizophrenia and more1. M1 PAMs have little to no agonistic properties, avoiding peripheral side effects, and are mostly centrally located allowing for the modulation of endogenous signaling of the brain2.MethodWe tested non‐human primates in two tasks measuring cognitive flexibility and attentional control3 at varying doses of donepezil and an M1 PAM (VU0453595). Attentional control was measured with a visual search task requiring animals to search for a learned target object among distractors of variable number and similarity to the target object. Cognitive flexibility was measured with a feature‐reward learning task that required animals to learn the value of objects of varying feature complexity by trial and error. Flexibility was indexed as the speed of learning, the degree of latent inhibition and the amount of target perseveration after switching the rewarded feature.ResultDonepezil enhanced attention control at a high dose (0.3 mg/kg) but enhance flexibility only moderately at a lower dose (0.06 mg/kg). In contrast, VU0453595 did not modulate attention, but at 0.1 mg/kg enhanced flexible learning, reduced target perseverations, and increased reaction time measures of decision confidence. At the dose with the most pronounced cognitive benefits donepezil resulted in gastrointestinal side effects, while VU0453595 did not cause side effects.ConclusionThese results suggest that donepezil engages the brain networks underlying cognitive flexibility and interference control at different doses4, while the M1 receptor plays a major role in facilitating flexible behavioral adaptation but with no role in controlling interference. Such receptor specific results can be used to better curate to patient‐specific needs in order to address the most debilitating symptoms with the highest efficacy.1. Melancon, B. J. et al. (2013) Drug Discovery Today https://doi.org/10.1016/j.drudis.2013.09.005.2. Ghoshal, A. et al. (2016) Neuropsychopharmacology doi:10.1038npp.2015.189 3. Womelsdorf, T. et al. (2021) Frontiers in Behavioral Neuroscience https://doi.org/10.3389/fnbeh.2021.721069 4. Hassani, S.A. et al. (2021) Biological Psychiatry Global Open Science https://doi.org/10.1016/j.bpsgos.2021.11.012.