GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse.
Sebastien Carnicella, Viktor Kharazia, Jerome Jeanblanc, Patricia H Janak, Dorit Ron
Proceedings of the National Academy of Sciences of the United States of America June 10, 2008 DOI: 10.1073/pnas.0711755105 via PubMed
Summary
Infusing GDNF directly into the ventral tegmental area (VTA) of rats rapidly and dose-dependently reduces their operant self-administration of alcohol, but not sucrose. This effect is specific to the VTA, as infusion into the neighboring substantia nigra does not alter alcohol responding. GDNF activates the MAPK signaling pathway in the VTA, and blocking this pathway prevents the reduction in alcohol self-administration. GDNF also blocks the reacquisition of alcohol self-administration after extinction, indicating it reduces relapse-like behavior. The findings suggest GDNF, via MAPK activation, acts as a fast-acting and selective agent to diminish alcohol consumption and seeking.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Keywords | Alcoholism treatment Gdnf Addiction neuroscience Pharmacotherapy |
| Citations | 132 |
| Key finding | GDNF infusion into the VTA rapidly and dose-dependently reduces alcohol self-administration and blocks relapse-like behavior in rats, an effect mediated by the MAPK signaling pathway. |
Abstract
Previously, we demonstrated that the action of the natural alkaloid, ibogaine, to reduce alcohol (ethanol) consumption is mediated by the glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area (VTA). Here we set out to test the actions of GDNF in the VTA on ethanol-drinking behaviors. We found that GDNF infusion very rapidly and dose-dependently reduced rat ethanol, but not sucrose, operant self-administration. A GDNF-mediated decrease in ethanol consumption was also observed in rats with a history of high voluntary ethanol intake. We found that the action of GDNF on ethanol consumption was specific to the VTA as infusion of the growth factor into the neighboring substantia nigra did not affect operant responses for ethanol. We further show that intra-VTA GDNF administration rapidly activated the MAPK signaling pathway in the VTA and that inhibition of the MAPK pathway in the VTA blocked the reduction of ethanol self-administration by GDNF. Importantly, we demonstrate that GDNF infused into the VTA alters rats' responses in a model of relapse. Specifically, GDNF application blocked reacquisition of ethanol self-administration after extinction. Together, these results suggest that GDNF, via activation of the MAPK pathway, is a fast-acting selective agent to reduce the motivation to consume and seek alcohol.