NMDA ANTAGONIST PROPERTIES OF THE PUTATIVE ANTIADDICTIVE DRUG, IBOGAINE

Both anecdotal reports in humans and preclinical studies indicate that ibogaine interrupts addiction to a variety of abused substances inclu ding alcohol, opiates, nicotine and stimulants. Based on the similarit y of these therapeutic claims to recent preclinical studies demonstrat ing that N-methyl-D-aspartate (NMDA) antagonists attenuate addiction-r elated phenomena, we examined the NMDA antagonist properties of ibogai ne. Pharmacologically relevant concentrations of ibogaine produce a vo ltage-dependent block of NMDA receptors in hippocampal cultures (K-i, 2.3 mu M at -60 mV). Consistent with this observation, ibogaine compet itively inhibits [H-3]1-[1-(2-thienyl)-cyclohexyl]piperidine binding t o rat forebrain homogenates (K-i, 1.5 mu M) and blocks glutamate-induc ed cell death in neuronal cultures (IC50, 4.5 mu M). Moreover, at dose s previously reported to interfere with drug-seeking behaviors, ibogai ne substitutes as a discriminative stimulus (ED(50), 64.9 mg/kg) in mi ce trained to discriminate the prototypic voltage-dependent NMDA antag onist, dizocilpine (0.17 mg/kg), from saline. Consistent with previous reports, ibogaine reduced naloxone-precipitated jumping in morphine-d ependent mice (ED(50), 72 mg/kg). Although pretreatment with glycine d id not affect naloxone-precipitated jumping in morphine-dependent mice , it abolished the ability of ibogaine to block naloxone-precipitated jumping. Taken together, these findings link the NMDA antagonist actio ns of ibogaine to a putative ''antiaddictive'' property of this alkalo id, its ability to reduce the expression of morphine dependence.