The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters.
Simon Bulling, Klaus Schicker, Yuan-Wei Zhang, Thomas Steinkellner, Thomas Stockner, Christian W Gruber, Stefan Boehm, Michael Freissmuth, Gary Rudnick, Harald H. Sitte, Walter Sandtner
Journal of Biological Chemistry May 25, 2012 DOI: 10.1074/jbc.m112.343681 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Intervention | Ibogaine |
| Topics | Ibogaine Serotonin |
| Keywords | Opiate withdrawal treatment Opioid addiction Substance abuse Detoxification Addiction recovery Therapeutic potential Brain chemistry Serotonin transporters Dopamine transporters Neurotransmitters Novel mechanism Noncompetitive inhibition External site Internal pathway Inward-open state Unique action Transporter modulation Drug discovery Fascinating discovery Crucial insight |
| Citations | 124 |
| Key findings | Ibogaine noncompetitively inhibits serotonin and dopamine transporters by binding to a distinct external site on the inward-open conformation, unlike competitive inhibitors such as cocaine. |
Abstract
Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study.
Comparable studies
Other experimental studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. In vitro (SERT) | 2007 | Laboratory study | |
| Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. | 1992 | Laboratory study | |
| Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. | 1995 | Experimental study | |
| Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity. | 1995 | Laboratory study | |
| The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex. Cells | 1994 | Laboratory study |
Citations in the library
Cited by 38
- Novel psychoactive substances of interest for psychiatry World Psychiatry February 1, 2016
- Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. Nature May 1, 2019
- Unique and potent effects of acute ibogaine on zebrafish: the developing utility of novel aquatic models for hallucinogenic drug research. Behavioural Brain Research 2013
- Structure-based discovery of conformationally selective inhibitors of the serotonin transporter. Cell May 11, 2023
- Conformational dynamics of the human serotonin transporter during substrate and drug binding. Nature Communications April 11, 2019
and 33 more in the library
Cites 7
- Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. Journal of Biological Chemistry October 5, 2007
- A review of chemical agents in the pharmacotherapy of addiction. Current Medicinal Chemistry October 1, 2002
- In Vivo Neurobiological Effects of Ibogaine and Its O-Desmethyl Metabolite, 12-Hydroxyibogamine (Noribogaine), in Rats Journal of Pharmacology and Experimental Therapeutics May 1, 2001
- Ibogaine attenuation of morphine withdrawal in mice: role of glutamate N-methyl-D-aspartate receptors. Progress in Neuro-Psychopharmacology and Biological Psychiatry August 1, 2003
- The effects of ibogaine on dopamine and serotonin transport in rat brain synaptosomes. Brain Research Bulletin April 1, 1999
and 2 more in the library