18-Methoxycoronaridine (18-MC) and ibogaine: comparison of antiaddictive efficacy, toxicity, and mechanisms of action.
18-MC, a novel iboga alkaloid congener, is being developed as a potential treatment for multiple forms of drug abuse. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a nondrug reinforcer (water). Both ibogaine and 18-MC ameliorate opioid withdrawal signs. Both ibogaine and 18-MC decrease extracellular levels of dopamine in the nucleus accumbens, but only ibogaine increases extracellular levels of serotonin in the nucleus accumbens. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the nucleus accumbens; only ibogaine enhances cocaine-induced increases in accumbal dopamine. Both ibogaine and 18-MC enhance the locomotor and/or stereotypic effects of stimulants. Ibogaine attenuates, but 18-MC potentiates, the acute locomotor effects of morphine; both compounds attenuate morphine-induced locomotion in morphine-experienced rats. Ibogaine produces whole body tremors and, at high doses (> or = 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, decreases heart rate at high doses. While 18-MC and ibogaine have similar affinities for kappa opioid and possibly nicotinic receptors, 18-MC has much lower affinities than ibogaine for NMDA and sigma-2 receptors, sodium channels, and the 5-HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. The data suggest that 18-MC has a narrower spectrum of actions and will have a substantially greater therapeutic index than ibogaine.
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Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA. glicks@mail.amc.edu
Maisonneuve
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D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D009020:Morphine; D011600:Psychopharmacology / Q000379:methods; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy*
D007050:Ibogaine; D009020:Morphine; D003042:Cocaine; C103345:18-methoxycoronaridine