Dose-Dependent Dissociation of Pro-cognitive Effects of Donepezil on Attention and Cognitive Flexibility in Rhesus Monkeys

Seyed A Hassani; Sofia Lendor; Adam Neumann; Kanchan Sinha Roy; Kianoush Banaie Boroujeni; Kari L Hoffman; Janusz Pawliszyn; Thilo Womelsdorf

doi:10.1016/j.bpsgos.2021.11.012

Dose-Dependent Dissociation of Pro-cognitive Effects of Donepezil on Attention and Cognitive Flexibility in Rhesus Monkeys

Biol Psychiatry Glob Open Sci. 2021 Dec 10;3(1):68-77. doi: 10.1016/j.bpsgos.2021.11.012. eCollection 2023 Jan.

Authors

Seyed A Hassani¹, Sofia Lendor², Adam Neumann¹, Kanchan Sinha Roy², Kianoush Banaie Boroujeni¹, Kari L Hoffman¹, Janusz Pawliszyn², Thilo Womelsdorf^{1

3}

Affiliations

¹ Department of Psychology, Vanderbilt University, Nashville, Tennessee.
² Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada.
³ Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.

Abstract

Background: Donepezil exerts pro-cognitive effects by nonselectively enhancing acetylcholine (ACh) across multiple brain systems. Two brain systems that mediate pro-cognitive effects of attentional control and cognitive flexibility are the prefrontal cortex and the anterior striatum, which have different pharmacokinetic sensitivities to ACh modulation. We speculated that these area-specific ACh profiles lead to distinct optimal dose ranges for donepezil to enhance the cognitive domains of attention and flexible learning.

Methods: To test for dose-specific effects of donepezil on different cognitive domains, we devised a multitask paradigm for nonhuman primates that assessed attention and cognitive flexibility. The nonhuman primates received either vehicle or variable doses of donepezil before task performance. We measured intracerebral donepezil and its strength in preventing the breakdown of ACh within the prefrontal cortex and anterior striatum using solid phase microextraction neurochemistry.

Results: The highest administered donepezil dose improved attention and made the subjects more robust against distractor interference, but it did not improve flexible learning. In contrast, only a lower dose range of donepezil improved flexible learning and reduced perseveration, but without distractor-dependent attentional improvement. Neurochemical measurements confirmed a dose-dependent increase of extracellular donepezil and decreases in choline within the prefrontal cortex and the striatum.

Conclusions: The donepezil dose for maximally improving attention differed from the dose range that enhanced cognitive flexibility despite the availability of the drug in two major brain systems supporting these functions. These results suggest that in our cohort of adult monkeys, donepezil traded improvements in attention for improvements in cognitive flexibility at a given dose range.

Keywords: Acetylcholine; Neurochemistry; Prefrontal cortex; Solid phase microextraction; Stability-flexibility trade-off; Striatum.

Grants and funding

R01 MH129641/MH/NIMH NIH HHS/United States