BEHAVIORAL AND BIOCHEMICAL-EVIDENCE FOR A NONESSENTIAL 5-HT2A COMPONENT OF THE IBOGAINE-INDUCED DISCRIMINATIVE STIMULUS

In the present investigation, the ability of two known hallucinogens, lysergic acid dimethylamide (LSD) and (-)-2,5-dimethoxp-4-methyl-amphe tamine (DOM), to substitute for the ibogaine-induced discriminative st imulus (10 mg/kg IP, 60 min presession) was assessed in Fischer-344 ra ts. In these subjects, intermediate levels of generalization were obse rved to both agents (LSD, 63%; DOM, 66.4%). This intermediate generali zation was completely blocked by pretreatment with the 5-HT2A antagoni st pirenpirone, suggesting that the ibogaine-like effects of these age nts are mediated by the 5-HT2A receptor. However, pirenpirone did not antagonize ibogaine itself, nor did it antagonize the ibogaine-like ef fects of harmaline and 12-hydroxyibogamine amine (noribogaine). To fur ther evaluate the serotonergic properties of ibogaine, in vivo protect ion assays and in vitro binding assays were employed. Micromolar 5 HT2 A affinity was observed with ibogaine (92.5 mu M), 12-hydroxyibogamine (34.5 mu M), and harmaline (42.5 mu M). Despite the apparently low af finity of these agents, both ibogaine and harmaline, but not 12-hydrox yibogamine, produced significant protection from receptor alkylation b y N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) when given 60 min prior to this alkylating agent. The results of these studies sugge st that although ibogaine may produce some of its effects via interact ions with 5-HT2A receptors, these do not appear to be essential to the ibogaine-induced discriminative stimulus. (C) 1998 Elsevier Science I nc.