Rapid and brief tolerance to (+)- and (-)-nicotine in unanesthetized rats

When given intravenously to unanesthetized rats as a bolus dose, (-)-nicotine produced a dose-related rise in blood pressure and fall in heart rate in the dose range of 5-40 micrograms/kg. Tolerance did not develop when doses were given at 30 min intervals. At the highest dose, the effects on heart rate persisted. In addition, severe arrhythmias and apnea were observed. (+)-Nicotine at 100 micrograms/kg produced effects similar to 10 micrograms/kg of (-)-nicotine. When given at 1 min intervals, tolerance quickly developed after only 6 injections at 5 micrograms/kg and after 4 injections at 10 micrograms/kg. Tolerance to (+)-nicotine also developed rapidly and was no longer evident at 5 min. The results suggest the tolerance is related to frequency of administration and dose. The implication of these results are discussed with regard to cardiovascular disease and dependence. In addition, we postulate that the relatively low degree of biological stereoselectivity of the optical isomers of nicotine, compared with that of the enantiomers of morphine, is due to the simplicity and flexibility of the nicotine molecule. It can be shown using Dreiding models that the nitrogen atoms in the enantiomers are nearly superimposable.