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Published on: October 29, 2012
Ibogaine acts at the nicotinic acetylcholine receptor to inhibit catecholamine release
1Department of Pharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
Insights
Ibogaine, an anti-addiction drug, selectively inhibits catecholamine release via nicotinic acetylcholine receptors at low doses. This action, not mediated by opioid receptors, suggests a key mechanism for its potential therapeutic effects in addiction treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Addiction Research
Background:
- Ibogaine is a putative anti-addiction agent.
- Its precise mechanisms of action, particularly concerning catecholamine release, require elucidation.
- Potential interactions with kappa opioid receptors have been suggested.
Purpose of the Study:
- To investigate the effects of ibogaine on catecholamine release in a neuronal model.
- To determine if ibogaine's actions are mediated by nicotinic acetylcholine receptors or kappa opioid receptors.
- To explore the dose- and time-dependency of ibogaine's effects.
Main Methods:
- Cultured bovine chromaffin cells were used as a model neuronal system.
- Catecholamine release was stimulated via nicotinic acetylcholine receptor activation, membrane depolarization (high K+), and veratridine.
- The effects of ibogaine were tested in the presence and absence of kappa opioid receptor antagonists (nor-binaltorphimine, naltrexone).
Main Results:
- Low concentrations of ibogaine (<10 microM) selectively inhibited nicotinic receptor-mediated catecholamine release.
- Ibogaine did not significantly affect release induced by veratridine or high K+.
- Inhibitory effects were not reversed by kappa opioid antagonists, indicating non-opioid mediation.
- Low-dose ibogaine effects were rapidly reversible; high-dose effects were persistent.
- Results suggest a mechanism involving the nicotinic acetylcholine receptor cation channel.
Conclusions:
- Ibogaine's anti-addictive properties may stem from its selective inhibition of catecholamine release at nicotinic acetylcholine receptors.
- The findings support a model where initial high ibogaine concentrations act broadly, followed by selective action at nicotinic receptors.
- These results are significant for understanding ibogaine's therapeutic potential and developing novel anti-nicotine addiction drugs.
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.
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