The effects of sigma, PCP, and opiate receptor ligands in rats trained with ibogaine as a discriminative stimulus.

Ibogaine, a hallucinogen with potential for treating addiction, produces its effects through interactions with multiple brain receptors. In rats trained to recognize ibogaine, ligands targeting sigma2 and opiate receptors partially reproduced ibogaine's effects, while sigma1-selective agents did not. Morphine and kappa-selective opioids failed to substitute for ibogaine, but mixed-action opiates like (-)-SKF 10,047 and nalorphine showed intermediate generalization. Naloxone partially blocked ibogaine's effects and fully blocked those of (-)-SKF 10,047 and nalorphine. Neither PCP nor MK-801 substituted for ibogaine, indicating NMDA receptors are not involved. The findings suggest that sigma2 and opiate receptors, but not NMDA receptors, contribute to ibogaine's discriminative stimulus.

Study at a glance

Abstract

Although the mechanism of action of ibogaine, a hallucinogen that may be useful in the treatment of addiction, remains unknown, receptor binding studies suggest that ibogaine produces its effects via interactions with multiple receptor types. In addition to serotonergic receptors, which have been studied previously with respect to ibogaine, likely candidates include opiate, sigma (sigma), and phencyclidine (PCP) binding sites. In an attempt to determine which of these receptor interactions are involved in the in vivo effects of ibogaine, ligands for sigma, PCP, and opiate receptors were assessed for their ability to substitute for or to antagonize the ibogaine-induced discriminative stimulus (10 mg/kg I.P., 60 min presession) in Fischer-344 rats. Intermediate levels of generalization were observed with the subtype nonselective sigma ligands 3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP] (69.0%) and 1,3-di(2-tolyl)guanidine (DTG) (73.5%) but not with the sigma1-selective agents (+)-N-allylnormetazocine [(+)-SKF 10,047] and (+)-pentazocine. These findings, along with observations that ibogaine has appreciable affinity for sigma2 receptors, suggest that these receptors may be involved in the ibogaine discriminative stimulus. With regard to opiate receptors, neither morphine, the prototypic mu agonist, nor kappa selective agonists (bremazocine,and U-50488) substituted for ibogaine. However, intermediate levels of generalization were observed with the mixed action opiates (-)-SKF 10,047 (78.9%), (+/-)-pentazocine (73.9%), nalorphine (70.4%), and diprenorphine (75.0%) indicating a potential role for opiate receptors in the ibogaine stimulus. Partial substitution was also observed with naltrexone (55.6%) but not with naloxone or the selective kappa antagonist nor-binaltorphimine (nor-BNI). These agents were largely ineffective as antagonists of the ibogaine cue, although naloxone produced a moderate but statistically significant antagonism (69.8%). In addition, naloxone produced complete antagonism of the ibogaine-appropriate responding elicited by both (-)-SKF 10,047 (19.7%) and nalorphine (25.8%), whereas the ibogaine-appropriate responding produced by diprenorphine was only partially antagonized (44.4%). The latter observations taken together with the finding that both nalorphine (>100 microM) and diprenorphine (30 microM) have extremely low affinity for sigma2 receptors, suggest that the ibogaine-appropriate responding produced by these agents is not mediated by sigma2 receptors. These findings imply that opiate effects may be involved in the ibogaine stimulus. In contrast to sigma2 and opiate receptors, ibogaine's reported interactions with NMDA receptors do not appear to be involved in its discriminative stimulus, as neither PCP nor MK-801 produced a significant level of ibogaine-appropriate responding. Thus, the present study offers evidence that unlike NMDA receptors, both sigma2 and opiate receptors may be involved in the ibogaine discriminative stimulus.