Antagonism of alpha 3 beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration.
European journal of pharmacology – March 01, 2002
Source: PubMed
Summary
Targeting specific brain receptors offers a new path to combat addiction. Research investigated how compounds, particularly 18-methoxycoronaridine, block alpha 3 beta 4 nicotinic receptors. Experiments revealed that low-dose combinations of these blockers significantly reduced both opioid and stimulant self-administration, even when individual doses were ineffective. This indicates that blocking these receptors is a promising strategy to reduce drug-seeking behavior, with 18-methoxycoronaridine showing great promise as a selective agent for future anti-addiction therapies.
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.