Cognition‐enhancing effects of nicotine, GTS‐21, donepezil and memantine on object retrieval in cynomolgus monkeys

Abstract

The development and validation of tests of executive function are of paramount importance to preclinical efforts in cognition. Object retrieval assesses attention and response inhibition mediated by the prefrontal cortex, and may be a valuable tool in this process. The current experiments evaluated the sensitivity of the object retrieval task to drugs used in the treatment of Alzheimer’s Disease. In this task, a transparent box, open on one side, is baited with a treat and presented to adult male cynomolgus monkeys. Two types of trials are presented: easy trials with direct reaches, and difficult trials with detour reaches. The nonselective nACh agonist nicotine (0.1–0.3 mg/kg i.m.), the selective nACh α7 agonist GTS-21 (0.01–0.3 mg/kg i.m.), the AChE inhibitor donepezil (0.03–0.1 mg/kg i.m. and 0.3–1.8 mg/kg p.o.), and the NMDA noncompetitive antagonist memantine (0.56–1.8 mg/kg p.o.) dose-dependently increased performance during difficult trials. By comparison, the nonselective mACh antagonist scopolamine (0.01–0.03 mg/kg i.m.) decreased performance during difficult trials, and this impairment was reversed by donepezil. Taken together, these results demonstrate that object retrieval is sensitive to the cognition-enhancing effects of both cholinergic and glutamatergic drugs effective in the treatment of Alzheimer’s Disease.