Autoregulation of glial cell line-derived neurotrophic factor expression: implications for the long-lasting actions of the anti-addiction drug, Ibogaine.

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.

Study at a glance

Abstract

We recently showed that the up-regulation of the glial cell line-derived neurotrophic factor (GDNF) pathway in the midbrain, is the molecular mechanism by which the putative anti-addiction drug Ibogaine mediates its desirable action of reducing alcohol consumption. Human reports and studies in rodents have shown that a single administration of Ibogaine results in a long-lasting reduction of drug craving (humans) and drug and alcohol intake (rodents). Here we determine whether, and how, Ibogaine exerts its long-lasting actions on GDNF expression and signaling. Using the dopaminergic-like SHSY5Y cell line as a culture model, we observed that short-term Ibogaine exposure results in a sustained increase in GDNF expression that is mediated via the induction of a long-lasting autoregulatory cycle by which GDNF positively regulates its own expression. We show that the initial exposure of cells to Ibogaine or GDNF results in an increase in GDNF mRNA, leading to protein expression and to the corresponding activation of the GDNF signaling pathway. This, in turn, leads to a further increase in the mRNA level of the growth factor. The identification of a GDNF-mediated, autoregulatory long-lasting feedback loop could have important implications for GDNF's potential value as a treatment for addiction and neurodegenerative diseases.