Combining tacrine with milameline reverses a scopolamine-induced impairment of continuous performance in rhesus monkeys

Abstract

  Rationale: Cholinomimetic therapy in Alzheimer’s disease (AD) has been hampered by narrow efficacious dose ranges and dose-limiting side effects. These limitations highlight the need for an alternative therapeutic approach for the symptomatic treatment of AD. Objectives: To determine in rhesus monkeys if combined treatment with the acetylcholinesterase inhibitor tacrine (Cognex) and the muscarinic agonist milameline improve behavioral efficacy in a scopolamine-reversal task without potentiating adverse side effects. Methods: Behavioral performance of rhesus monkeys was measured using a continuous performance task. The effects of tacrine and milameline, separately or in combination, were determined following administration of an impairing dose of the anticholinergic scopolamine. In addition, tacrine and milameline were given similarly in the absence of scopolamine to determine the presence of adverse side effects. Results: Tacrine and milameline, separately or in combination, reversed the scopolamine-induced decrease in responses on a continuous performance task. Administered in combination, tacrine and milameline significantly improved performance on this task at lower doses and across a broader dose range than when given separately. In the absence of scopolamine, combined treatment did not potentiate the appearance of side effects or produce adverse events significantly different from those observed with either compound alone. Conclusions: Tacrine and milameline given in combination broadened the range of doses significantly reversing a scopolamine-induced impairment without potentiating adverse side effects.