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

Pharmacol Biochem Behav. 1998 Feb;59(2):419-25. doi: 10.1016/s0091-3057(97)00451-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkylating Agents / pharmacology
  • Animals
  • Behavior, Animal / drug effects*
  • Brain Chemistry / drug effects*
  • DOM 2,5-Dimethoxy-4-Methylamphetamine / pharmacology
  • Discrimination, Psychological / drug effects*
  • Dose-Response Relationship, Drug
  • Hallucinogens / pharmacology*
  • Ibogaine / pharmacology*
  • Kinetics
  • Lysergic Acid Diethylamide / pharmacology
  • Male
  • Rats
  • Rats, Inbred F344
  • Receptors, Serotonin / drug effects*
  • Serotonin Antagonists / pharmacology

Substances

  • Alkylating Agents
  • Hallucinogens
  • Receptors, Serotonin
  • Serotonin Antagonists
  • DOM 2,5-Dimethoxy-4-Methylamphetamine
  • Ibogaine
  • Lysergic Acid Diethylamide