The goal of the proposed research is to gain understanding of the pathophysiological activities of ethanol in the brain, by studying the effects of ethanol on the NR2 subunits of the ionotropic glutamate N-methyl D-Aspartate (NMDA) receptor channel. The NMDA receptor is a heteromer comprised of the obligatory NR1 subunit and different combination of NR2 subunits (NR2A-D), with the major subunits in the brain being NR2A and NR2B. The cytoplasmic tails of NR2A and NR2B are phosphorylated by the tyrosine kinases Fyn or Src, and phosphorylation modulates the activity of the channel. The NMDA receptor is an important mediator of the activities of ethanol in the brain. Miyakawa and colleagues have reported that systemic administration of ethanol in mice results in tyrosine phosphorylation of hippocampal NR2B by Fyn kinase (Miyakawa et. al., 1997). Similarly, we have found that ethanol leads to phosphorylation of NR2B on tyrosine residues in isolated rat hippocampal slice preparations. We therefore hypothesize that induction of NR2B and possibly NR2A phosphorylation will play an important role in the pathophysiological effects of ethanol. In this study we propose to pursue four specific goals in an effort to better understand the biochemical, physiological and behavioral consequences of ethanol exposure mediated through the NMDA receptor system. First, we will study the spatial and temporal localization of ethanol induced NMDA receptor tyrosine phosphorylation in the brain. Second, we will examine the role of kinases and scaffolding proteins in ethanol induced NMDA receptor phosphorylation. Third, we will characterize the physiological consequences of ethanol induced NMDA receptor phosphorylation. Finally, we will test possible behavioral consequences of ethanol-induced NMDA receptor phosphorylation. Our long term goal is to understand the molecular mechanism of ethanol activities that contribute to the development of disease states associated with alcoholism, in order identify targets for the development of new medications to treat alcoholism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Sorensen, Roger
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ernest Gallo Clinic and Research Center
United States
Zip Code
Legastelois, RĂ©mi; Darcq, Emmanuel; Wegner, Scott A et al. (2015) Striatal-enriched protein tyrosine phosphatase controls responses to aversive stimuli: implication for ethanol drinking. PLoS One 10:e0127408
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
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
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
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
Ron, Dorit; Messing, Robert O (2013) Signaling pathways mediating alcohol effects. Curr Top Behav Neurosci 13:87-126
Wang, Jun; Ben Hamida, Sami; Darcq, Emmanuel et al. (2012) Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: implications for alcohol drinking behavior. J Neurosci 32:15124-32
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
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

Showing the most recent 10 out of 20 publications