METABOLITES OF NICOTINE IN RAT-BRAIN AFTER PERIPHERAL NICOTINE ADMINISTRATION - COTININE, NORNICOTINE, AND NORCOTININE

The time course of nicotine metabolite appearance in brain from 5 min- 18 hr after subcutaneous administration of S-(-)-[H-3-N-methyl]nicotin e was determined. Results demonstrated that metabolite appearance in b rain was greatest at 4 hr postadministration, whereas levels of nicoti ne were greatly diminished at this time point. For determination of N- demethylated metabolites, (+/-)-[2'-C-14]nicotine was administered sub cutaneously to rats, and the presence of nicotine and nicotine metabol ites in brain supernatant was determined 4 hr postadministration. Usin g high-performance liquid radiochromatographic analysis, nicotine and three nicotine metabolites (cotinine, nornicotine, and norcotinine) we re identified in brain, together with a fourth minor, unidentified met abolite. After subcutaneous administration of S-(-)-[G-H-3]cotinine, s ignificant amounts of cotinine were found in brain over an 18-hr posta dministration period; however, no cotinine metabolites were detected. Therefore, cotinine is able to pass the blood-brain barrier and access the central nervous system, but is not biotransformed in brain. Thus, this is the first report of norcotinine as a central nervous system n icotine metabolite. Data indicate that norcotinine detected in brain a fter peripheral nicotine administration most likely originates from 5' -C-oxidation of brain nornicotine, rather than from N-demethylation of cotinine, as occurs peripherally. Because peripheral biotransformatio n of nicotine to nornicotine is a minor pathway, the relatively high l evels of nornicotine found in brain after peripheral nicotine administ ration suggest that nornicotine is formed via oxidative N-demethylatio n of nicotine locally in brain. Nornicotine is pharmacologically activ e; thus, its presence in brain after peripheral nicotine administratio n indicates that nornicotine may contribute to the neuropharmacologica l effects of nicotine and tobacco use.