Wettstein, J. G. | Search bioRxiv

bioRxiv2025

Pharmacological Reversal of Attention Deficits in Non-Human Primates: Implications for Alzheimer's Disease

Attention deficits emerge early in Alzheimers disease (AD), where cholinergic dysfunction compromises goal-directed behavior and cognitive control. Therefore, attentional impairments may serve as early indicators of cognitive decline, and also as meaningful targets for therapeutic intervention. Despite their clinical importance, attention deficits remain under- targeted by current treatments, which offer only modest benefit. To support development of more effective therapies, preclinical models that closely mirror human neurobiology and behavior are essential. Non-human primates (NHPs), with their high degree of cortical and functional similarity to humans, particularly in prefrontal regions, offer a uniquely translational platform for evaluating cognitive enhancers. We assessed pharmacological interventions targeting sustained attention using the Continuous Performance Test (CPT) in adult male cynomolgus macaques. Monkeys were trained to detect target stimuli while ignoring distractors, achieving individualized stable performance. To simulate cholinergic dysfunction, we administered scopolamine, a muscarinic acetylcholine receptor antagonist, which produced dose-dependent declines in accuracy and reaction time. Mild and severe impairment levels were identified within each animal. We then tested three compounds: nicotine, guanfacine, and donepezil. Nicotine, a nicotinic receptor agonist, fully restored performance across both impairment levels, suggesting potential benefit in both early and advanced AD. Guanfacine, an 2A adrenergic agonist, improved accuracy only under mild impairment, while donepezil, an acetylcholinesterase inhibitor, showed inconsistent effects. None of the compounds reversed scopolamine-induced slowing of reaction time, indicating specificity for attentional control. These findings highlight the utility of the NHP CPT as a pharmacologically sensitive model for detecting attentional dysfunction and evaluating pro-cognitive therapeutics in aging and neurodegeneration.

animal behavior and cognition↗

bioRxiv2025

Behavioral and Pharmacological Validation of the Differential Reinforcement of Low-Rate Behavior Paradigm in Non-Human Primates

Depression remains a leading cause of disability worldwide, yet the predictive validity of many preclinical behavioral assays for antidepressant efficacy remains limited. The Differential Reinforcement of Low-Rate Behavior (DRL) task has classically been used in rodents to identify antidepressant-like effects, but its utility in non-human primates (NHPs) has not been established. Here, we adapted the DRL task for use in adult male cynomolgus macaques (Macaca fascicularis) and evaluated its pharmacological sensitivity and translational relevance across 19 compounds spanning multiple drug classes. Antidepressants, including SSRIs, SNRIs, NRIs, NDRIs, TCAs, MAOIs, and PDE4 inhibitors, generally shifted DRL performance in an antidepressant-like direction, increasing reinforcers earned and inter-response times while decreasing response output. In contrast, benzodiazepine and antipsychotic control compounds did not produce a consistent antidepressant-like profile, whereas stimulant effects were mixed, with nicotine and cocaine also producing overlapping antidepressant-like behavioral effects. Importantly, the primate DRL task identified antidepressant-like effects of PDE4 inhibitors while also capturing emesis, a dose-limiting side effect not observable in rodent models. These findings support the primate DRL task as a translationally relevant platform for screening antidepressant-like efficacy, while also highlighting important design considerations for interpreting pharmacological sensitivity in the NHP setting. By modeling behavioral processes implicated in depression, including response inhibition and temporal regulation, this assay offers a unique opportunity to bridge preclinical and clinical antidepressant development with improved sensitivity to both efficacy and tolerability.

animal behavior and cognition↗