Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs

Cocaine and a number of 3 beta-phenyltropane cocaine analogs were investiga ted for their potential to block various pharmacological effects of nicotin e in animals. They blocked the antinociceptive effect of nicotine in the ta il-flick test after systemic administration in a dose-dependent manner. Sim ilarly, cocaine was also able to block nicotine-induced motor impairment in mice. Furthermore, cocaine blocked nicotine-induced seizures at a lower po tency than for antinociception, but failed to block nicotine's effect on bo dy temperature and drug discrimination. The antagonistic potencies of the 3 beta-phenyltropane cocaine analogs were not correlated with their affinity for monoamines transporters. Additionally, bupropion, nomifensin, GBR 1290 9, and nisoxetine, but not methylphenidate and fluoxetine, blocked nicotine -induced antinociception; however, their antagonistic potencies were unrela ted to their affinities for the transporters. Taken together, these results suggest that the mechanism of cocaine's antagonistic activity is not relat ed to its binding and uptake of inhibition on monoamine neurotransporters. The failure of lidocaine and procaine to antagonize nicotine's effects in t he tail-flick assay rules out local anesthetic effects. In addition, cocain e blocked differentially the response of nicotine in the oocyte receptor ex pression system for the alpha(4)beta(2) and alpha(3)beta(2) subtypes in a d ose-dependent manner. Our results suggest that cocaine is a noncompetitive nicotinic antagonist with some selectivity for neuronal nicotinic receptor subtypes. Our studies also demonstrate that 3 beta-phenyltropane analogs co nstitute a new class of nicotinic antagonists. Elucidation of the mechanism of action of this new class of antagonists may provide an explanation for the effectiveness of agents such as bupropion for the treatment of smoking cessation.