Abstract
The putative anti-addiction alkaloid ibogaine and its principal metabolite 12-hydroxyibogamine appear to act at the (+)-5 methyl-10,11-dihydro-5
H-dibenzo[
a,d]cycloheten-5–10-imine maleate (MK-801) binding site in the
N-methyl-
d-aspartate (NMDA)-receptor cation channel. This conclusion is based on findings that both compounds competitively displaced specific [
3H]MK-801 binding to membranes from postmortem human caudate and cerebellum and from frog spinal cord. Ibogaine was 4–6 fold more potent than its metabolite and both compounds were less potent (50–1000-fold) than MK-801 binding to the NMDA receptor. In addition, ibogaine (100 μM) and 12-hydroxyibogamine (1 mM) blocked (85–90% of control) the ability of NMDA (100μM, 5 s) to depolarize frog motoneurons in the isolated frog spinal cord. The prevention of NMDA-depolarizations in frog motoneurons showed use-dependency and was very similar to the block produced by MK-801. In view of the abilities of MK-801 to affect the responses to addictive substances in pre-clinical investigations, our results are compatible with the idea that the ability of ibogaine and 12-hydroxyibogamine to interrupt drug-seeking behavior may, in part, result from their actions at the MK-801 binding site.
