Behavioral and biochemical evidence for a nonessential 5-HT2A component of the ibogaine-induced discriminative stimulus.

In rats trained to recognize the hallucinogen ibogaine, two other hallucinogens—LSD and DOM—partially substituted for ibogaine (63% and 66.4% of responses, respectively). This partial substitution was completely blocked by the 5-HT2A antagonist pirenpirone, indicating that LSD and DOM produce ibogaine-like effects through the 5-HT2A receptor. However, pirenpirone did not block ibogaine itself or its effects from harmaline and noribogaine. Ibogaine, noribogaine, and harmaline showed only micromolar affinity for the 5-HT2A receptor (92.5, 34.5, and 42.5 µM). Ibogaine and harmaline, but not noribogaine, protected the receptor from alkylation. The findings suggest that while ibogaine interacts with 5-HT2A receptors, these interactions are not essential for its discriminative stimulus effects.

Study at a glance

Abstract

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.