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 cholinergic neurons, especially when the release of acetylcholine is increased. In the present study we applied the microdialysis technique to measure the concentration of extracellular choline in the rat hippocampus. The i.p. injection of 6, 20 and 60 mg/kg of choline chloride led to short-lasting elevations of the basal choline efflux (1.78 pmol/min) by 14, 26 and 131%. N-Methylnicotinamide, a metabolite of nicotinamide, has 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 dramatically potentiated the effects of exogenous choline administration on choline availability in the central nervous system. The effects of 6 and 20 mg/kg of choline chloride were increased by a factor of more than 10-fold when determined as area under the curve. Additional experiments demonstrated that neither nicotinamide nor N-methylnicotinamide (100 microM) have an influence on the uptake, metabolism or release of choline in the hippocampal slice preparation. It is likely, therefore, that nicotinamide, after metabolic conversion in the brain to N-methylnicotinamide, 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 cholinergic dysfunction.