S(-)-Nornicotine Increases Dopamine Release in a Calcium-Dependent Manner from Superfused Rat Striatal Slices


Address correspondence and reprint requests to Dr. L. P. Dwoskin at Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, University of Kentucky, Rose Street, Lexington, KY 40536-0082, U.S.A.


Abstract: The present study demonstrates that S(-)-nornicotine evoked a concentration-dependent increase in dopamine (DA) release from superfused rat striatal slices. The increase in DA release was indicated by an S(-)-nornicotine-induced overflow of endogenous 3,4-dihydroxyphenyl-acetic acid (DOPAC) in the striatal superfusate and by an S(-)-nornicotine-induced increase in tritium overflow from striatal slices preloaded with [3H]DA. Low concentrations (0.01–1.0 μM) of S(-)-nornicotine, which did not evoke endogenous DOPAC overflow, also were unable to modulate electrically evoked DOPAC overflow. The increase in DOPAC overflow induced by S(-)-nornicotine was compared with that produced by S(-)-nicotine. Comparing equimolar concentrations (0.1-100 μM) of S(-)-nornicotine and S(-)-nicotine, superfusion with S(-)-nornicotine resulted in a significantly greater DOPAC overflow. In contrast to the effect of S(-)-nicotine, S(-)-nornicotine evoked a sustained increase in DOPAC over-flow for the entire period of S(-)-nornicotine exposure. Furthermore, DOPAC overflow evoked by S(-)-nornicotine in control Krebs buffer was inhibited by superfusion with a low-calcium buffer. Moreover, in the low-calcium buffer, DOPAC overflow induced by 30 and 100 μM S(-)-nornicotine was not different from that with no S(-)-nornicotine. The results indicate that S(-)-nornicotine, a constituent of tobacco products and a known metabolite of S(-)-nicotine, increases DA release in a calcium-dependent manner in superfused rat striatal slices. It is interesting that unlike S(-)-nicotine, there does not appear to be desensitization to this effect of S(-)-nornicotine.