Modulation of nicotine self-administration in rats by combination therapy with agents blocking alpha 3 beta 4 nicotinic receptors.

18-Methoxycoronaridine, a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In previous work, 18-methoxycoronaridine was found to be a somewhat selective antagonist at alpha3beta4 nicotinic receptors; and low dose combinations of 18-methoxycoronaridine with other drugs known to have the same action (e.g., mecamylamine, dextromethorphan) decreased both morphine and methamphetamine self-administration in rats at doses that were ineffective if administered alone. In the present study, similar drug combinations (but including bupropion as well) were found to decrease nicotine self-administration in rats. The data further support the hypothesis that diencephalic pathways having high densities of alpha3beta4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of alpha3beta4 nicotinic receptors may represent a totally novel approach to treating polydrug abuse.