Mechanisms of Antiaddictive Actions of Ibogainea.

Ibogaine, an alkaloid from Tabemanthe iboga, can decrease morphine and cocaine self-administration for several days in some rats, with shorter-lasting effects on ethanol and nicotine intake. Both ibogaine and its metabolite noribogaine acutely lower dopamine levels in the nucleus accumbens. Ibogaine pretreatment blocks morphine-induced dopamine release and hyperactivity but enhances similar effects of stimulants like cocaine and amphetamine. The compound binds to kappa opioid, NMDA, serotonin, sigma-2, and nicotinic receptors. Kappa agonist and NMDA antagonist actions appear to contribute to ibogaine's effects on opioid and stimulant self-administration, while serotonergic actions may be more important for reducing alcohol intake. Nicotinic antagonist action may mediate reduced nicotine preferences, and sigma-2 action appears to mediate neurotoxicity.

Study at a glance

Abstract

Ibogaine, an alkaloid extracted from Tabemanthe iboga, is being studied as a potential long-acting treatment for oploid and stimulant abuse as well as for alcoholism and smoking. Studies in this laboratory have used animal models to characterize ibogaine's interactions with drugs of abuse, and to investigate the mechanisms responsible. Ibogaine, as well as its metabolite, noribogaine, can decrease both morphine and cocaine self-administration for several days in some rats; shorter-lasting effects appear to occur on ethanol and nicotine intake. Acutely, both ibogaine and noribogaine decrease extracellular levels of dopamine in the nucleus accumbens of the rat brain. Ibogaine pretreatment (19 hours beforehand) blocks morphine-induced dopamine release and morphine-induced locomotor hyperactivity while, in contrast, it enhances similar effects of stimulants (cocaine and amphetamine). Ibogaine pretreatment also blocks nicotine-induced dopamine release. Both ibogaine and noribogaine bind to kappa opioid and N-methyl-d-aspartate (NMDA) receptors and to serotonin uptake sites; ibogaine also binds to sigma-2 and nicotinic receptors. The relative contributions of these actions are being assessed. Our ongoing studies in rats suggest that kappa agonist and NMDA antagonist actions contribute to ibogaine's effects on opioid and stimulant self-administration, while the serotonergic actions may be more important for ibogaine-induced decreases in alcohol intake. A nicotinic antagonist action may mediate ibogaine-induced reduction of nicotine preferences in rats. A sigma-2 action of ibogaine appears to mediate its neurotoxicity. Some effects of ibogaine (e.g., on morphine and cocaine self-administration, morphine-induced hyperactivity, cocaine-induced increases in nucleus accumbens dopamine) are mimicked by a kappa agonist (U50,488) and/or a NMDA antagonist (MK-801). Moreover, a combination of a kappa antagonist and a NMDA agonist will partially reverse several of ibogaine's effects. Ibogaine's long-term effects may be mediated by slow release from fat tissue (where ibogaine is sequestered) and conversion to noribogaine. Different receptors, or combinations of receptors, may mediate interactions of ibogaine with different drugs of abuse.