SYNERGISTIC EFFECT OF NICOTINAMIDE AND CHOLINE ADMINISTRATION ON EXTRACELLULAR CHOLINE LEVELS IN THE BRAIN

Experimental studies indicate that the availability of free choline is a rate-limiting step for acetylcholine synthesis in central cholinerg ic neurons, especially when the release of acetylcholine is increased. In the present study we applied the microdialysis technique to measur e the concentration of extracellular choline in the rat hippocampus. T he i.p. injection of 6, 20 and 60 mg/kg of choline chloride led to sho rt-lasting elevations of the basal choline efflux (1.78 pmol/min) by 1 4, 26 and 131 %. N-Methylnicotinamide, a metabolite of nicotinamide, h as been reported to inhibit the outward transport of choline from the cerebrospinal fluid to the blood. The s.c. injection of 5 and 10 mmol/ kg of nicotinamide caused increases of extracellular choline by 54 and 113%, respectively, and choline levels remained elevated for several hr. Moreover, the administration of 10 mmol/kg of nicotinamide dramati cally potentiated the effects of exogenous choline administration on c holine availability in the central nervous system. The effects of 6 an d 20 mg/kg of choline chloride were increased by a factor of more than 10-fold when determined as area under the curve. Additional experimen ts demonstrated that neither nicotinamide nor N-methylnicotinamide (10 0 muM) have an influence on the uptake, metabolism or release of choli ne in the hippocampal slice preparation. It is likely, therefore, that nicotinamide, after metabolic conversion in the brain to N-methylnico tinamide, leads to a blockade of choline clearance from the brain. The combined administration of choline and of a choline transport blocker analogous to nicotinamide may be of potential use in central choliner gic dysfunction.