Our long-term goal is to test the hypothesis that growth factors such as the glial cell line-derived neurotrophic factor (GDNF) counteract the adverse actions of alcohol and thus prevent or delay the development of alcohol addiction. In the first round of funding we found that the activation of the GDNF pathway in the midbrain dopaminergic ventral tegmental area (VTA) rapidly attenuates the motivation for, and relapse to, ethanol consumption. Using a multidisciplinary approach, we plan to elucidate the mechanism underlying the actions of GDNF to reduce consumption of ethanol.
In Aim 1, we will examine whether GDNF in the VTA possesses intrinsic rewarding or stimulant properties.
In Aim 2, we will determine whether GDNF adjusts the excitability of VTA neurons in a rat model of long-term excessive ethanol consumption.
In Aim 3 we will test if GDNF in the VTA modifies the neuroadaptations in dopamine levels in the nucleus accumbens resulting from excessive ethanol consumption.
In Aim 4, we will elucidate the molecular mechanism responsible for GDNF's action to attenuate ethanol-drinking behaviors. Alcoholism is a devastating disease that manifests itself in uncontrolled consumption. Identifying signaling pathways that inhibit this phenotype, such as the ones activated by GDNF, are therefore of great interest, as this will likely lead to the identification of new targets for medication development to treat alcoholism, and may also lead to the identification of genetic risk factors for the disease.

Public Health Relevance

Alcoholism is a devastating disease that affects approximately 14 million people per year in the USA alone. Unfortunately, only limited numbers of drugs are currently approved by the FDA to treat adverse phenotypes associated with the disease. Therefore, there is a great need to identify novel targets for medication development. We found that the growth factor GDNF is a negative regulator of alcohol-drinking behaviors and relapse. Therefore, GDNF and its downstream effector proteins are potential drug targets to treat alcoholism. Here, we plan to elucidate the mechanism by which GDNF regulates alcohol's actions. Results generated from these studies may lead to development of novel, selective agents to treat alcohol abuse.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-A (02))
Program Officer
Cui, Changhai
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Ernest Gallo Clinic and Research Center
United States
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Ron, Dorit; Barak, Segev (2016) Molecular mechanisms underlying alcohol-drinking behaviours. Nat Rev Neurosci 17:576-91
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
Logrip, Marian L; Barak, Segev; Warnault, Vincent et al. (2015) Corticostriatal BDNF and alcohol addiction. Brain Res 1628:60-7
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
Carnicella, Sebastien; Ron, Dorit; Barak, Segev (2014) Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse. Alcohol 48:243-52
Becker, Howard C; Ron, Dorit (2014) Animal models of excessive alcohol consumption: recent advances and future challenges. Alcohol 48:205-8
Ahmadiantehrani, Somayeh; Ron, Dorit (2013) Dopamine D2 receptor activation leads to an up-regulation of glial cell line-derived neurotrophic factor via Gβγ-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
Ron, Dorit; Messing, Robert O (2013) Signaling pathways mediating alcohol effects. Curr Top Behav Neurosci 13:87-126

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