Vol. 304, Issue 3, 1268-1274, March 2003

Active Transport of High-Affinity Choline and Nicotine Analogs into the Central Nervous System by the Blood-Brain Barrier Choline Transporter

David D. Allen, Paul R. Lockman, Karen E. Roder, Linda P. Dwoskin and Peter A. Crooks

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University HSC, Amarillo, Texas (D.D.A., P.R.L., K.E.R.); and Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.P.D., P.A.C.)

Cigarette smoking is strongly implicated in the development of cardiovascular disorders. Recently identified nicotinium analogs may have therapeutic benefit as smoking cessation therapies but may have restricted entry into the central nervous system by the blood-brain barrier (BBB) due to their physicochemical properties. Using the in situ perfusion technique, lobeline, choline, and nicotinium analogs were evaluated for binding to the BBB choline transporter. Calculated apparent K_i values for the choline transporter were 1.7 µM N-n-octyl choline, 2.2 µM N-n-hexyl choline, 27 µM N-n-decylnicotinium iodide, 31.9 µM N-n-octylpyridinium iodide, 49 µM N-n-octylnicotinium iodide (NONI), 393 µM lobeline, and 1000 µM N-methylnicotinium iodide. Nicotine and N-methylpyridinium iodide, however, do not apparently interact with the BBB choline transporter. Given NONI's apparent K_i value determined in this study and its ability to inhibit nicotine-evoked dopamine release from superfused rat brain slices, potential brain entry of NONI via the BBB choline transporter was evaluated. [³H]NONI exhibited a BBB transfer coefficient value of ~1.6 × 10³ ml/s/g and a K_m of ~250 µM. Unlabeled choline addition to the perfusion fluid reduced [³H]NONI brain uptake. We hypothesize the N-n-octyl group on the pyridinium nitrogen of NONI facilitates brain entry via the BBB choline transporter. Thus, NONI may have utility as a smoking cessation agent, given its ability to inhibit nAChRs mediating nicotine-evoked dopamine release centrally, and to be distributed to brain via the BBB choline transporter.