R-(1) and S-(2) Isomers of Cotinine Augment Cholinergic Responses In Vitro and In Vivo

The nicotine metabolite cotinine (1-methyl-5-[3-pyridynl]-2pyrrolidinone), like its precursor, has been found to exhibit procognitive and neuroprotective effects in somemodel systems; however, the mechanism of these effects is unknown. In this study, both the R-(1) and S-(2) isomers of cotinine were initially evaluated in an extensive profiling screen and found to be relatively inactive across a wide range of potential pharmacologic targets. Electrophysiological studies on human a4b2 and a7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes confirmed the absence of agonistic activity of cotinine at a4b2 ora7 nAChRs. However, a significant increase in the current evoked by a low concentration of acetylcholine was observed at a7 nAChRs exposed to 1.0mMR-(1)orS-(2)-cotinine. Based on these results, we used a spontaneous novel object recognition (NOR) procedure for rodents to test the hypothesis that R-(1)or S-(2)-cotinine might improve recognition memory when administered alone or in combination with the Alzheimer’s disease (AD) therapeutic agent donepezil. Although both isomers enhanced NOR performance when they were coadministered with donepezil, neither isomer was active alone. Moreover, the procognitive effects of the drug combinations were blocked by methyllycaconitine and dihydro-b-erythroidine, indicating that both a7 and a4b2 nAChRs contribute to the response. These results indicate that cotinine may sensitize a7 nAChRs to low levels of acetylcholine (a previously uncharacterized mechanism), and that cotinine could be used as an adjunctive agent to improve the effective dose range of cholinergic compounds (e.g., donepezil) in the treatment of AD and other memory disorders.