Dose-dependent dissociation of pro-cognitive effects of donepezil on attention and cognitive flexibility in rhesus monkeys

Abstract

BACKGROUND Donepezil exerts pro-cognitive effects by non-selectively 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 multi-task paradigm for nonhuman primates (NHPs) that assessed attention and cognitive flexibility. NHPs received either vehicle or variable doses of donepezil prior to task performance. We measured donepezil intracerebral and how strong it prevented the breakdown of ACh within prefrontal cortex and anterior striatum using solid-phase-microextraction neurochemistry. RESULTS The highest administered donepezil dose improved attention and made 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 small cohort of adult monkeys donepezil traded improvements in attention for improvements in cognitive flexibility at a given dose range.