EFFECTS OF IBOGA ALKALOIDS ON MORPHINE AND COCAINE SELF-ADMINISTRATION IN RATS - RELATIONSHIP TO TREMORIGENIC EFFECTS AND TO EFFECTS ON DOPAMINE RELEASE IN NUCLEUS-ACCUMBENS AND STRIATUM

Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addiction to opioid and stimulant drugs and has been reported to decrease morphine and cocaine self-administration in rats. The present study sought to determine if other iboga alkaloids, as well as the chemically related harmala alkaloid harmaline, would also reduce the intravenous self-administration of morphine and cocaine in rats. Because both ibogaine and harmaline induce tremors, an effect that may be causally related to neurotoxicity in the cerebellar vermis, the temorigenic activities of the other iboga alkaloids were assessed. Lastly, in view of the involvement of the dopaminergic mesolimbic system in the actions of drugs of abuse, the effects of some of the iboga alkaloids on extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum were determined. All of the tested alkaloids (i.e., ibogaine, tabernanthine, R- and S-coronaridine, R- and S-ibogamine, desethylcoronaridine, and harmaline) dose-dependently (2.5-80 mg/kg) decreased morphine and cocaine intake in the hour after treatment; decreases in morphine and cocaine intake intake were also apparent the day after administration of some but not all of these alkaloids (i.e., ibogaine, tabernanthine, desethylcoronaridine, and the R-isomers of coronaridine and ibogamine). In some rats, there were persistent decreases in morphine or cocaine intake for several days after a single injection or after two or three weekly injections of one or another of these alkaloids; R-ibogamine produced such effects more consistently than any of the other alkaloids. At the doses used to assess effects on drug self-administration, ibogaine, tabernanthine, desethylcoronaridine and harmaline all induced tremors for at least 2-3 h; both enantioners of both coronaridine and ibogamine induced very weak no tremors. Using in vivo microdialysis, the effects of the R- and S-enantiomers of coronaridine and ibogamine on extracellular dopamine levels in the nucleus accumbaens and striatum were compared. The R-entantiomers decreased dopamine levels in both brain regions whereas the S-enantiomers produced no significant changes in dopamine levels in either region. The results of this study indicate that the 'anti-addictive' and tremorigenic effects of the iboga alkaloids can be dissociated and that long-term effects of these alkaloids on drug self-administration appear to be related to initial decreases in dopaminergic activity in specific brain areas.