Autoregulation of glial cell line-derived neurotrophic factor expression: implications for the long-lasting actions of the anti-addiction drug, Ibogaine.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology – November 01, 2006
Source: PubMed
Summary
A single dose of a promising anti-addiction drug can have remarkably long-lasting effects. Research reveals this drug initiates a unique self-sustaining process. Scientists investigated how this drug causes sustained changes in a crucial brain protein, GDNF, known to reduce cravings. Using cell models, they found the drug triggers GDNF to boost its own production in a continuous, positive feedback cycle. This discovery highlights GDNF's significant potential for treating addiction and neurodegenerative diseases.
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.