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
Sd. Glick et al., 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, Brain research, 657(1-2), 1994, pp. 14-22
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.