The centrally acting cholinesterase inhibitor tacrine was compared with three nicotinic acetylcholine receptor (nAChR) agonists for their abilities to enhance performance of mature adult macaques performing a computer-automated version of the delayed matching-to-sample (DMTS) task. All four drugs enhanced DMTS performance at one or more doses, although ABT-418 [(S)-3-methyl-5-(l-methyl-2-pyrrolidinyl) isoxazole] may be the most potent and the most effective of the four. Nicotine was less potent and less effective than ABT-418 but was more potent than either tacrine or isoarecolone. At each animal's respective maximally effective dose, task improvement ranged from approximately 14 to 30% over vehicle performance levels. Despite the significantly enhanced levels of performance improvement obtained on the day of drug administration, when the animals were tested 24 h later (in the absence of drug), only nicotine-treated animals exhibited a significant improvement in performance. In an attempt to help explain this protracted improvement in DMTS performance to nicotine, cell surface nerve growth factor (NGF) receptors were measured in cultured PC-12 cells before and after exposure to nicotine. Exposure to nicotine for 24 h resulted in a significant increase in cell surface NGF in the cells. However, even after nicotine was removed from the culture medium, NGF receptor protein continued to increase for an additional 24 h. The results of this study are consistent with the possibility that stimulation of central nAChRs may be employed to improve cognitive function in cognitively impaired individuals. They also suggest that one potential mechanism for the protracted beneficial effect of nicotine may involve the enhanced expression of brain NGF receptors. Drug Dev.