Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin.
Ibogaine is a hallucinogenic indole with putative efficacy for the treatment of cocaine, stimulant and opiate abuse. The purported efficacy of ibogaine following single dose administrations has led to the suggestion that a long-acting metabolite of ibogaine may explain in part how the drug reduces craving for psychostimulants and opiates. We report here that 12-hydroxyibogamine, a primary metabolite of ibogaine, displays high affinity for the 5-HT transporter and elevates extracellular 5-HT. In radioligand binding assays, 12-hydroxyibogamine was 50-fold more potent at displacing radioligand binding at the 5-HT transporter than at the DA transporter. Ibogaine and 12-hydroxyibogamine were equipotent at the dopamine transporter. In vivo microdialysis was used to evaluate the acute actions of ibogaine and 12-hydroxyibogamine on the levels of DA and 5-HT. Administration of 12-hydroxyibogamine produced a marked dose-related elevation of extracellular 5-HT. Ibogaine and 12-hydroxyibogamine failed to elevate DA levels in the nucleus accumbens over the dose range tested. The elevation in synaptic levels of 5-HT by 12-hydroxyibogamine may heighten mood and attenuate drug craving. The effects of the active metabolite on 5-HT transmission may account in part for the potential of ibogaine to interrupt drug-seeking behavior in humans.
Mash
D C
DC
Dept. of Neurology, University of Miami School of Medicine, FL 33136, USA.
Staley
J K
JK
Baumann
M H
MH
Rothman
R B
RB
Hearn
W L
WL
D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007050:Ibogaine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D013057:Spectrum Analysis
D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D007050:Ibogaine; D004298:Dopamine