The effects of sigma, PCP, and opiate receptor ligands in rats trained with ibogaine as a discriminative stimulus.
Scott Helsley, R A Filipink, W D Bowen, R A Rabin, Jerrold C Winter
Pharmacology, Biochemistry, and Behavior February 1, 1998 DOI: 10.1016/s0091-3057(97)00454-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Fischer-344 rats |
| Interventions | ibogaine 3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine 1 3-di(2-tolyl)guanidine (+)-N-allylnormetazocine (+)-pentazocine morphine bremazocine U-50488 (-)-SKF 10 047 (+/-)-pentazocine nalorphine diprenorphine naltrexone naloxone nor-binaltorphimine PCP MK-801 |
| Dose | 10 mg/kg I.P. |
| Topics | Ibogaine |
| Keywords | Ibogaine compound Ibogaine action Ibogaine effects Addiction treatment Substance abuse treatment Therapeutic potential Addiction therapy Neuropharmacology Brain pathways Receptor mechanisms Drug action Mechanism of action Neurobiology Sigma2 receptors Sigma-2 receptors Sigma receptors Opiate receptors Opioid receptors Opiate pathways |
| Citations | 16 |
| Key points | Sigma2 and opiate receptors, but not NMDA receptors, appear to mediate ibogaine's discriminative stimulus in rats. |
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.
Comparable studies
Other preclinical and animal studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Noncompetitive Functional Inhibition at Diverse, Human Nicotinic Acetylcholine Receptor Subtypes by Bupropion, Phencyclidine, and Ibogaine TE671/RD cells (human muscle-type nAChR) and SH-SY5Y neuroblastoma cells (human... | 1999 | In vitro study | |
| Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. Ibogaine- or harmaline-treated rats | 1993 | Experimental animal study | |
| Effects and aftereffects of ibogaine on morphine self-administration in rats. Rats | 1991 | Preclinical experimental study | |
| Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Rats | 1994 | Experimental study | |
| Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption Rats | 2005 | Experimental study |
Citations in the library
Cited by 11
- Noribogaine is a G-protein biased κ-opioid receptor agonist. Neuropharmacology December 1, 2015
- IUPHAR - invited review - Ibogaine - A legacy within the current renaissance of psychedelic therapy. Pharmacological Research April 1, 2023
- Noribogaine generalization to the ibogaine stimulus: correlation with noribogaine concentration in rat brain. Neuropsychopharmacology July 1, 1999
- Characterization of the discriminable stimulus produced by 2-BFI: effects of imidazoline I(2)-site ligands, MAOIs, beta-carbolines, agmatine and ibogaine. British Journal of Pharmacology March 1, 2002
- Ibogaine and Noribogaine: Comparing Parent Compound to Metabolite CNS Drug Reviews September 1, 2000
and 6 more in the library
Cites 28
- Effects and aftereffects of ibogaine on morphine self-administration in rats. European Journal of Pharmacology April 3, 1991
- Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Brain Research September 19, 1994
- A preliminary investigation of ibogaine: case reports and recommendations for further study. Journal of Substance Abuse Treatment 1994
- Ibogaine possesses a selective affinity for sigma 2 receptors. Life Sciences 1995
- Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. Brain Research February 7, 1992
and 23 more in the library