Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and in vitro laboratory study
PubMed 15659598 · doi:10.1523/JNEUROSCI.3959-04.2005
What was done
The authors evaluated the effect of ibogaine on ethanol self-administration in rats using two-bottle choice and operant self-administration paradigms, including a relapse model. To identify the underlying mechanism, they microinjected ibogaine into the ventral tegmental area (VTA) or substantia nigra, measured midbrain glial cell line-derived neurotrophic factor (GDNF) expression after systemic ibogaine administration, and tested GDNF pathway activation (phosphorylation of Ret and ERK1) in dopaminergic neuron-like SHSY5Y cells. They also tested whether intra-VTA microinjection of GDNF mimicked, and intra-VTA anti-GDNF neutralizing antibodies blocked, ibogaine's effect on ethanol intake.
What was found
The abstract reports directional findings without numerical values or effect sizes. Ibogaine decreased rat ethanol intake in two-bottle choice, operant self-administration, and relapse models. Microinjection of ibogaine into the VTA, but not the substantia nigra, decreased ethanol self-administration. Systemic ibogaine increased GDNF expression in a midbrain region including the VTA, and ibogaine upregulated GDNF pathway signaling in SHSY5Y cells via increased phosphorylation of Ret and ERK1. Intra-VTA GDNF microinjection mimicked ibogaine's reduction of ethanol intake, and intra-VTA anti-GDNF neutralizing antibodies reduced the ibogaine-mediated effect.
Why it matters
This study identifies midbrain GDNF upregulation as a key molecular mechanism mediating ibogaine's reduction of alcohol self-administration in rodents. This points to GDNF signaling as a target for developing alcoholism therapeutics that avoid the adverse side effects of ibogaine.
Limits
The study is restricted to rodent models and cell culture, precluding direct conclusions about human safety or efficacy. The abstract reports no sample sizes, quantitative data, statistical values, or effect sizes. Adverse effects, potential toxicity, and long-term durability of the intervention were not reported in the abstract.
Cited by
- supports Administering ibogaine to rodents trained to self-administer alcohol causes them to stop self-administering alcohol.
- supports Injecting glial-derived neurotrophic factor (GDNF) directly into the ventral tegmental area of rodents causes them to stop self-administering alcohol.
- supports Injecting ibogaine directly into the ventral tegmental area stops alcohol self-administration in rodents.