Effects of nornicotine enantiomers on intravenous S(−)-nicotine self-administration and cardiovascular function in rats
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Previous neurochemical evidence indicates that R(+)-nornicotine is more potent than S(−)-nornicotine in evoking dopamine release in rat nucleus accumbens slices.
The current study tested the hypothesis that R(+)-nornicotine is also more potent than S(−)-nornicotine in selectively decreasing intravenous S(−)-nicotine self-administration in rats.
After acute pretreatment (1–10 mg/kg for each enantiomer), R(+)-nornicotine was more potent than S(−)-nornicotine in decreasing S(−)-nicotine self-administration; in contrast, within the same dose range, the nornicotine enantiomers were equipotent in decreasing sucrose-maintained responding. This enantioselectivity does not likely reflect a difference in bioavailability, since similar levels of nornicotine were recovered from the brain 60 min after injection (5.6 mg/kg for each enantiomer). With repeated pretreatment, tolerance did not develop to the rate-decreasing effect of either nornicotine enantiomer (3 or 5.6 mg/kg) with respect to the decrease in S(−)-nicotine self-administration, although the enantioselectivity dissipated across repeated pretreatments. While both enantiomers acutely produced a similar increase in blood pressure and heart rate, tolerance developed to the blood pressure effects of R(+)-nornicotine, but not to the effects of S(−)-nornicotine, across repeated treatments.
Both R(+)- and S(−)-nornicotine may have potential utility as a novel tobacco use cessation agent.
KeywordsNornicotine Nicotine self-administration Cardiovascular effects Tobacco dependence Schedule-controlled behavior
This work was supported by USPHS grant DA 016521 to Yaupon Therapeutics. The University of Kentucky holds a patent for nornicotine as a smoking cessation therapy, and the patent is licensed to Yaupon Therapeutics, Inc. P.A.C, L.P.D. and M.T.B. have financial interests in Yaupon.