Ibogaine acts at the nicotinic acetylcholine receptor to inhibit catecholamine release.

Ibogaine, at low concentrations below 10 microM, selectively inhibits catecholamine release triggered by nicotinic acetylcholine receptor activation in cultured bovine chromaffin cells, while not affecting release caused by membrane depolarization or sodium channel activation. This inhibition is not reversed by kappa opioid receptor antagonists, indicating the effect is not mediated through kappa opioid receptors. The inhibition by low-dose ibogaine is rapidly reversible, whereas higher doses produce inhibition lasting at least 19 hours after removal. These findings suggest ibogaine acts at the nicotinic acetylcholine receptor, relevant to its potential anti-addictive effects and development of treatments for nicotine addiction.

Study at a glance

Abstract

In an effort to determine mechanisms of action of the putative anti-addictive agent ibogaine, we have measured its effects on catecholamine release in a model neuronal system, cultured bovine chromaffin cells. Various modes of stimulating catecholamine release were used including nicotinic ACh receptor activation, membrane depolarization with elevated K+ and Na+ channel activation with veratridine. In addition, because ibogaine has been reported to interact with kappa opioid receptors, we tested whether kappa receptor antagonists could reverse ibogaine's effects on catecholamine release. Ibogaine, at low concentration (<10 microM) was found to selectively inhibit nicotinic receptor-mediated catecholamine release, while having no significant effect on release evoked by either veratridine or membrane depolarization with elevated K+. The inhibitory actions of ibogaine and the kappa agonists were not reversed by preincubation with the opioid antagonists nor-binaltorphimine or naltrexone, suggesting that these inhibitory effects are not mediated by the kappa opioid receptor. The effects of low dose (10 microM) ibogaine were rapidly reversible, while the inhibitory effects of higher ibogaine doses persisted for at least 19 h following ibogaine washout. The results provide evidence for a mechanism of action ibogaine at the nicotinic ACh receptor. The results are consistent with a model in which the initial high transient brain concentrations (100 microM) of ibogaine act at multiple cellular sites and then have a selective action at the nicotinic ACh receptor cation channel following its metabolism to lower brain concentrations. The present findings are relevant to potential anti-addictive actions of ibogaine and to the development of drugs to combat nicotine addiction.