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 effec tive 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 we ll as the chemically related harmala alkaloid harmaline, would also re duce the intravenous self-administration of morphine and cocaine in ra ts. Because both ibogaine and harmaline induce tremors, an effect that may be causally related to neurotoxicity in the cerebellar vermis, th e temorigenic activities of the other iboga alkaloids were assessed. L astly, in view of the involvement of the dopaminergic mesolimbic syste m in the actions of drugs of abuse, the effects of some of the iboga a lkaloids on extracellular levels of dopamine and its metabolites in th e nucleus accumbens and striatum were determined. All of the tested al kaloids (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 tr eatment; decreases in morphine and cocaine intake intake were also app arent the day after administration of some but not all of these alkalo ids (i.e., ibogaine, tabernanthine, desethylcoronaridine, and the R-is omers of coronaridine and ibogamine). In some rats, there were persist ent decreases in morphine or cocaine intake for several days after a s ingle injection or after two or three weekly injections of one or anot her of these alkaloids; R-ibogamine produced such effects more consist ently than any of the other alkaloids. At the doses used to assess eff ects on drug self-administration, ibogaine, tabernanthine, desethylcor onaridine and harmaline all induced tremors for at least 2-3 h; both e nantioners of both coronaridine and ibogamine induced very weak no tre mors. Using in vivo microdialysis, the effects of the R- and S-enantio mers 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-enantio mers produced no significant changes in dopamine levels in either regi on. The results of this study indicate that the 'anti-addictive' and t remorigenic effects of the iboga alkaloids can be dissociated and that long-term effects of these alkaloids on drug self-administration appe ar to be related to initial decreases in dopaminergic activity in spec ific brain areas.