Accumulation of nicotine and its metabolites in rat brain after intermittent or continuous peripheral administration of [2 '-C-14] nicotine

Concentrations of nicotine, cotinine, and nornicotine in brain and blood fo llowing both intermittent and continuous administration of [2'-C-14] nicoti ne to rats were determined to assess nicotine metabolite accumulation in br ain following repeated nicotine administration. For intermittent studies, r ats were administered s.c. 1 to 10 doses of nicotine (0.3 mg/kg, 15 or 25 m u Ci of [2'-C-14] nicotine; 30-min interinjection interval). For continuous administration studies, rats were implanted s.c. with an osmotic minipump delivering nicotine (0.8 mg/kg/day, 25 or 50 mu Ci of [2'-C-14] nicotine fo r 1-21 days). Whole brain and trunk blood was collected. The concentration of [2'-C-14] nicotine and its metabolites was determined via high-pressure liquid radiochromatography. Brain concentrations of nicotine, cotinine, and nornicotine increased 2-, 12-, and 9-fold, respectively, following 10 inje ctions, reaching a plateau following the fifth injection. Brain blood ratio s indicate an enhanced preferential distribution of nornicotine to brain wi th increasing numbers of injections. Across the 21-day period of continuous infusion, blood nicotine and nornicotine concentrations remained relativel y constant, whereas concentrations in brain increased similar to4-fold. Gen erally, cotinine concentrations in brain and blood did not change across th e infusion period. Brain/blood ratios indicate an increase in nicotine dist ribution into brain across days of nicotine infusion. Results demonstrate t hat both nicotine and its metabolites accumulate in brain following repeate d nicotine administration, and indicate that brain nicotine concentration c an not be extrapolated from plasma cotinine or nicotine concentrations. Thu s, nornicotine accumulation following repeated nicotine administration sugg ests that this metabolite plays a contributory role in the neuropharmacolog ical effects of nicotine.