The long-term goal of our research is to test the hypothesis that post-translational modifications such as phosphorylation are major contributors to brain region-specific responses to alcohol exposure. In the first round of funding we found that the sensitivity of the N-methyl-D-Aspartate receptor (NMDAR) to ethanol in specific brain regions is determined by the activation state of the non-receptor tyrosine kinases Fyn (activation) and Src (inhibition), leading to changes in the phosphorylation state of the NR2B (Fyn) and NR2A (Src) subunits of the NMDAR. We found that these signaling alterations lead to profound changes in the activity of the NMDAR during and after acute exposure to ethanol in slice preparations and in vivo. More recently, we identified an important role for Fyn and NR2B-NMDAR in the dorsal striatum in the long-lasting facilitation of NR2B-containing NMDAR-mediated activity after ethanol exposure and in ethanol drinking behavior. The NMDAR is an important mediator of ethanol's actions in the brain, and our results suggest that changes in the activation state of the Fyn in the dorsal striatum contribute to aberrant synaptic plasticity that may underlie the development of behavioral phenotypes such as the propensity to consume ethanol. Using molecular, biochemical, electrophysiological and behavioral approaches, we propose to elucidate the mechanism leading to, and are the consequences of, ethanol-mediated Fyn activation in the dorsal striatum of rats. As Fyn activity is both positively and negatively regulated by phosphorylation, we will determine the contribution of the tyrosine phosphatases, PTPalpha and STEP, to ethanol's actions on Fyn activation, NR2B phosphorylation and long-term facilitation of NMDAR activity in vivo. Additionally, we plan to investigate possible physiological consequences of dorsal striatal activation of Fyn. Finally, we will determine the contribution of Fyn, PTPalpha, and STEP to operant ethanol self-administration in rats. Our long-term goal is to understand the molecular mechanisms that contribute to the development of disease states associated with alcohol addiction. Identification of new intracellular targets that are mediators of alcohol addiction is an essential future direction for the development of novel interventions for alcohol related disorders.

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. The ion channel NMDAR has attracted great interest as a potential drug target to treat alcoholism and other neurological diseases. Results generated from these studies may enable us to develop agents that modulate the activity of a subset population of the channel in specific areas of the brain, and therefore may lead to the development of novel, selective targets to treat alcohol abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA013438-10
Application #
8242765
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (02))
Program Officer
Cui, Changhai
Project Start
2001-12-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2012
Total Cost
$357,130
Indirect Cost
$143,023
Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608
Darcq, Emmanuel; Hamida, Sami Ben; Wu, Su et al. (2014) Inhibition of striatal-enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption. J Neurochem 129:1024-34
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
Ben Hamida, Sami; Darcq, Emmanuel; Wang, Jun et al. (2013) Protein tyrosine phosphatase * in the dorsomedial striatum promotes excessive ethanol-drinking behaviors. J Neurosci 33:14369-78
Sparta, Dennis R; Hopf, Frederic Woodward; Gibb, Stuart L et al. (2013) Binge ethanol-drinking potentiates corticotropin releasing factor R1 receptor activity in the ventral tegmental area. Alcohol Clin Exp Res 37:1680-7
Ron, Dorit; Messing, Robert O (2013) Signaling pathways mediating alcohol effects. Curr Top Behav Neurosci 13:87-126
Carnicella, Sebastien; Yowell, Quinn V; Ron, Dorit (2011) Regulation of operant oral ethanol self-administration: a dose-response curve study in rats. Alcohol Clin Exp Res 35:116-25
Wang, Jun; Lanfranco, Maria Fe; Gibb, Stuart L et al. (2011) Ethanol-mediated long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum. Channels (Austin) 5:205-9
Gibb, Stuart L; Hamida, Sami Ben; Lanfranco, Maria Fe et al. (2011) Ethanol-induced increase in Fyn kinase activity in the dorsomedial striatum is associated with subcellular redistribution of protein tyrosine phosphatase ?. J Neurochem 119:879-89
Wang, Jun; Lanfranco, Maria Fe; Gibb, Stuart L et al. (2010) Long-lasting adaptations of the NR2B-containing NMDA receptors in the dorsomedial striatum play a crucial role in alcohol consumption and relapse. J Neurosci 30:10187-98

Showing the most recent 10 out of 18 publications