Antagonism of alpha 3 beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration.

Ibogaine and a related compound, 18-methoxycoronaridine, block alpha 3 beta 4 nicotinic receptors in the brain, with 18-methoxycoronaridine being more selective for these receptors than ibogaine. Low doses of combinations of 18-methoxycoronaridine with mecamylamine or dextromethorphan, or mecamylamine with dextromethorphan, reduced morphine and methamphetamine self-administration in studies, even though each drug alone at those doses was ineffective. The findings suggest that blocking alpha 3 beta 4 receptors may help reduce drug-seeking behavior, and 18-methoxycoronaridine may represent a new class of anti-addiction agents.

Study at a glance

Abstract

The iboga alkaloid ibogaine and the novel iboga alkaloid congener 18-methoxycoronaridine are putative anti-addictive agents. Using patch-clamp methodology, the actions of ibogaine and 18-methoxycoronaridine at various neurotransmitter receptor ion-channel subtypes were determined. Both ibogaine and 18-methoxycoronaridine were antagonists at alpha 3 beta 4 nicotinic receptors and both agents were more potent at this site than at alpha 4 beta 2 nicotinic receptors or at NMDA or 5-HT(3) receptors; 18-methoxycoronaridine was more selective in this regard than ibogaine. In studies of morphine and methamphetamine self-administration, the effects of low dose combinations of 18-methoxycoronaridine with mecamylamine or dextromethorphan and of mecamylamine with dextromethorphan were assessed. Mecamylamine and dextromethorphan have also been shown to be antagonists at alpha 3 beta 4 nicotinic receptors. All three drug combinations decreased both morphine and methamphetamine self-administration at doses that were ineffective if administered alone. The data are consistent with the hypothesis that antagonism at alpha 3 beta 4 receptors is a potential mechanism to modulate drug seeking behavior. 18-Methoxycoronaridine apparently has greater selectivity for this site than other agents and may be the first of a new class of synthetic agents acting via this novel mechanism to produce a broad spectrum of anti-addictive activity.