The goal of this project is to study the role of the glial derived neurotrophic factor (GDNF) in alcohol addiction. Previous evidence suggests that activation of the GDNF pathway can reverse biochemical and behavioral adaptations to drugs of abuse. We found that the naturally occurring alkaloid Ibogaine, that possesses anti-addiction properties for drugs of abuse and alcohol, activates the GDNF pathway in vitro and in vivo. We further found that mutant mice that express 50% of the GDNF message consume more ethanol than their corresponding wild-type controls. Curiously, we also found that acute exposure of cells to ethanol, like GDNF or Ibogaine, induces the phosphorylation of the GDNF receptor tyrosine kinase, Ret, whereas chronic exposure to ethanol reduces the protein level of Ret. Based on these results we hypothesize that, acutely, ethanol activates the GDNF pathway as a homeostatic pathway that prevents or delays the development of neuroadaptations leading to addiction. We further hypothesize that when this homeostatic mechanism ceases functioning, the initiation of long-term molecular and morphological changes that lead to behaviors associated with the development of addiction occur. Using biochemical and behavioral approaches, this proposal will address both hypotheses.
In specific aim 1, we will test the hypothesis that the GDNF pathway is activated upon acute treatment of cells or mice with ethanol, and identify the mechanism by which acute ethanol induces the phosphorylation of the GDNF receptor Ret.
In specific aim 2, we will test the hypothesis that long-term ethanol treatment inhibits the GDNF pathway and we will identify the biochemical consequences of this inhibition.
In specific aim 3, we will test the hypothesis that activation of the GDNF pathway will reduce whereas inhibition of the GDNF pathway will enhance the reinforcing activities of ethanol in ethanol self-administration and relapse models. Our long-term goal is understand the function of growth factors such as GDNF in alcohol addiction. The information generated from these studies may elucidate novel pathways for the delay or prevention of adaptations to chronic alcohol and may lead to the development of new approaches for the treatment of alcohol addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA014366-04
Application #
7217537
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Noronha, Antonio
Project Start
2004-05-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$374,562
Indirect Cost
Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608
Barak, Segev; Ahmadiantehrani, Somayeh; Logrip, Marian L et al. (2018) GDNF and alcohol use disorder. Addict Biol :
Ron, Dorit; Barak, Segev (2016) Molecular mechanisms underlying alcohol-drinking behaviours. Nat Rev Neurosci 17:576-91
Logrip, Marian L; Barak, Segev; Warnault, Vincent et al. (2015) Corticostriatal BDNF and alcohol addiction. Brain Res 1628:60-7
Barak, Segev; Wang, Jun; Ahmadiantehrani, Somayeh et al. (2015) Glial cell line-derived neurotrophic factor (GDNF) is an endogenous protector in the mesolimbic system against excessive alcohol consumption and relapse. Addict Biol 20:629-42
Wang, Jun; Cheng, Yifeng; Wang, Xuehua et al. (2015) Alcohol Elicits Functional and Structural Plasticity Selectively in Dopamine D1 Receptor-Expressing Neurons of the Dorsomedial Striatum. J Neurosci 35:11634-43
Becker, Howard C; Ron, Dorit (2014) Animal models of excessive alcohol consumption: recent advances and future challenges. Alcohol 48:205-8
Carnicella, Sebastien; Ron, Dorit; Barak, Segev (2014) Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol 48:243-52
Ahmadiantehrani, Somayeh; Barak, Segev; Ron, Dorit (2014) GDNF is a novel ethanol-responsive gene in the VTA: implications for the development and persistence of excessive drinking. Addict Biol 19:623-33
Ahmadiantehrani, Somayeh; Ron, Dorit (2013) Dopamine D2 receptor activation leads to an up-regulation of glial cell line-derived neurotrophic factor via G??-Erk1/2-dependent induction of Zif268. J Neurochem 125:193-204
Davies, Daryl L; Bortolato, Marco; Finn, Deborah A et al. (2013) Recent advances in the discovery and preclinical testing of novel compounds for the prevention and/or treatment of alcohol use disorders. Alcohol Clin Exp Res 37:8-15

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