Ibogaine, a natural alkaloid with side effects that prevent clinical use, reduces alcohol consumption in rats. In two-bottle choice and operant self-administration tests, ibogaine decreased ethanol intake and also reduced relapse-like drinking. The effect is mediated by glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area (VTA): ibogaine microinjected into the VTA reduced self-administration, systemic ibogaine increased GDNF expression in the midbrain, and in dopaminergic SHSY5Y cells ibogaine activated the GDNF pathway (phosphorylation of Ret and ERK1). Intra-VTA GDNF mimicked ibogaine's effect, while anti-GDNF antibodies blocked it. GDNF in the VTA therefore mediates ibogaine's action on ethanol consumption, suggesting GDNF as a target for alcoholism medications that could avoid ibogaine's side effects.
A single dose of Ibogaine, a putative anti-addiction drug, triggers a sustained increase in glial cell line-derived neurotrophic factor (GDNF) in midbrain cells. Using cultured dopaminergic-like SHSY5Y cells, short-term Ibogaine exposure initiated a self-sustaining positive feedback loop: GDNF mRNA rose, protein was expressed, and the GDNF signaling pathway activated, which further increased GDNF mRNA. This autoregulatory cycle explains Ibogaine's long-lasting reduction of drug craving in humans and alcohol and drug intake in rodents. The discovery of this GDNF-mediated feedback loop suggests potential for GDNF-based treatments for addiction and neurodegenerative diseases.
A single dose of Ibogaine, a putative anti-addiction drug, triggers a sustained increase in glial cell line-derived neurotrophic factor (GDNF) in midbrain cells. Using cultured dopaminergic-like SHSY5Y cells, short-term Ibogaine exposure initiated a self-sustaining positive feedback loop: GDNF mRNA rose, protein was expressed, and the GDNF signaling pathway activated, which further increased GDNF mRNA. This autoregulatory cycle explains Ibogaine's long-lasting reduction of drug craving in humans and alcohol and drug intake in rodents. The discovery of this GDNF-mediated feedback loop suggests potential for GDNF-based treatments for addiction and neurodegenerative diseases.
Noribogaine, a metabolite of ibogaine, increases GDNF expression in cell cultures and reduces alcohol self-administration when infused into the ventral tegmental area (VTA) of rats, whereas 18-MC, a synthetic ibogaine derivative, does not affect GDNF expression or alcohol responding in the VTA. These findings indicate that noribogaine and 18-MC act through different mechanisms and brain sites to reduce alcohol consumption, and that noribogaine may share ibogaine's anti-addictive properties without some of its side effects.