In the present investigation, the ability of two known hallucinogens, lysergic acid
dimethylamide (LSD) and (-)-2,5-dimethoxy-4-methyl-amphetamine (DOM), to substitute
for the ibogaine-induced discriminative stimulus (10 mg/kg I.P., 60 min presession)
was assessed in Fischer-344 rats. In these subjects, intermediate levels of generalization
were observed to both agents (LSD, 63%; DOM, 66.4%). This intermediate generalization
was completely blocked by pretreatment with the 5-HT2A antagonist pirenpirone, suggesting
that the ibogaine-like effects of these agents are mediated by the 5-HT2A receptor.
However, pirenpirone did not antagonize ibogaine itself, nor did it antagonize the
ibogaine-like effects of harmaline and 12-hydroxyibogamine (noribogaine). To further
evaluate the serotonergic properties of ibogaine, in vivo protection assays and in
vitro binding assays were employed. Micromolar 5-HT2A affinity was observed with ibogaine
(92.5 microM), 12-hydroxyibogamine (34.5 microM), and harmaline (42.5 microM). Despite
the apparently low affinity of these agents, both ibogaine and harmaline, but not
12-hydroxyibogamine, produced significant protection from receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline
(EEDQ) when given 60 min prior to this alkylating agent. The results of these studies
suggest that although ibogaine may produce some of its effects via interactions with
5-HT2A receptors, these do not appear to be essential to the ibogaine-induced discriminative
stimulus.