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

Rationale: Cholinomimetic therapy in Alzheimer's disease (AD) has been hamp ered by narrow efficacious dose ranges and dose-limiting side effects. Thes e limitations highlight the need for an alternative therapeutic approach fo r the symptomatic treatment of AD. Objectives: To determine in rhesus monke ys if combined treatment with the acetylcholinesterase inhibitor tacrine (C ognex) and the muscarinic agonist milameline improve behavioral efficacy in a scopolamine-reversal task without potentiating adverse side effects. Met hods: Behavioral performance of rhesus monkeys was measured using a continu ous performance task. The effects of tacrine and milameline, separately or in combination, were determined following administration of an impairing do se of the anticholinergic scopolamine. In addition, tacrine and milameline were given similarly in the absence of scopolamine to determine the presenc e of adverse side effects. Results: Tacrine and milameline, separately or i n combination, reversed the scopolamine-induced decrease in responses on a continuous performance task. Administered in combination, tacrine and milam eline significantly improved performance on this task at lower doses and ac ross a broader dose range than when given separately. In the absence of sco polamine, combined treatment did not potentiate the appearance of side effe cts or produce adverse events significantly different from those observed w ith either compound alone. Conclusions Tacrine and milameline given in comb ination broadened the range of doses significantly reversing a scopolamine induced impairment without potentiating adverse side effects.