Tropisetron, a 5-HT3 receptor antagonist commonly prescribed for chemotherapy-induced nausea and vomiting also exhibits high affinity, partial agonist activity at alpha 7 nicotinic acetylcholine receptors (a7 nAChRs). alpha 7 nAChRs are considered viable therapeutic targets for neuropsychiatric disorders such as Alzheimer's disease (AD). Here we further explored the nAChR pharmacology of tropisetron to include the homomeric alpha 7 nAChR and recently characterized heteromeric alpha 7 beta 2 nAChR (1:10 ratio) and we evaluated its cognitive effects in young and aged animals. Electrophysiological studies on human nAChRs expressed in Xenopus oocytes confirmed the partial agonist activity of tropisetron at a7 nAChRs (EC50 similar to 2.4 mu M) with a similar effect at alpha 7 beta 2 nAChRs (EC50 similar to 1.5 mu M). Moreover, currents evoked by irregular pulses of acetylcholine (40 mu M) at a7 and alpha 7 beta 2 nAChRs were enhanced during sustained exposure to low concentrations of tropisetron (10 and 30 nM) indicative of a "priming" or co-agonist effect. Tropisetron (0.1-10 mg/kg) improved novel object recognition performance in young Sprague-Dawley rats and in aged Fischer rats. In aged male and female rhesus monkeys, tropisetron (0.03-1 mg/kg) produced a 17% increase from baseline levels in delayed match to sample long delay accuracy while combination of non-effective doses of donepezil (0.1 mg/kg) and tropisetron (0.03 and 0.1 mg/kg) produced a 24% change in accuracy. Collectively, these animal experiments indicate that tropisetron enhances cognition and has the ability to improve the effective dose range of currently prescribed AD therapy (donepezil). Moreover, these effects may be explained by tropisetron's ability to sensitize alpha 7 containing nAChRs to low levels of acetylcholine. (C) 2017 Elsevier Ltd. All rights reserved.