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The Journal of Neuroscience, March 28, 2007, 27(13):3593-3602; doi:10.1523/JNEUROSCI.4749-06.2007

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Neurobiology of Disease
Ethanol Induces Long-Term Facilitation of NR2B-NMDA Receptor Activity in the Dorsal Striatum: Implications for Alcohol Drinking Behavior

Jun Wang,¹ Sebastien Carnicella,¹ Khanhky Phamluong,¹ Jerome Jeanblanc,¹ Jennifer A. Ronesi,³ Nadia Chaudhri,¹ Patricia H. Janak,^1,2 David M. Lovinger,³ and Dorit Ron^1,2

¹Ernest Gallo Research Center, ²Department of Neurology, University of California, San Francisco, Emeryville, California 94608, and ³Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism–National Institutes of Health, Bethesda, Maryland 20892

Correspondence should be addressed to Dr. Dorit Ron, Ernest Gallo Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: dorit.ron{at}ucsf.edu

Addiction is characterized by compulsive alcohol or drug taking and seeking, and the dorsal striatum has been implicated in such maladaptive persistent habits. The NMDA receptor (NMDAR), which is a major target of alcohol, is implicated in striatal-based habit learning. We found that, in the dorsal striatum, alcohol (ethanol) exposure produced an increase in the phosphorylation of the NR2B subunit of the NMDAR, and a corresponding increase in the activity of Fyn kinase, which phosphorylates NR2B. We further observed an ethanol-mediated long-term facilitation (LTF) of the activity of NR2B-containing NMDARs (NR2B-NMDARs) in the dorsal striatum. This LTF is Fyn kinase dependent, because it was observed in Fyn wild-type but not in Fyn knock-out mice. Importantly, none of these biochemical and physiological changes was observed in the ventral striatum. Finally, dorsal but not ventral striatum infusion of a Fyn or NR2B-NMDAR inhibitor reduced rat operant self-administration of ethanol. Our results suggest that the Fyn-mediated phosphorylation and LTF of NR2B-NMDAR activity in the dorsal striatum after exposure to ethanol may underlie aberrant plasticity that contributes to mechanisms underlying alcohol drinking behavior.

Key words: accumbens; addiction; drinking; Fyn; NMDA receptors; self-administration; striatum; synaptic plasticity

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Received Oct. 31, 2006; revised March 2, 2007; accepted March 5, 2007.

Correspondence should be addressed to Dr. Dorit Ron, Ernest Gallo Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: dorit.ron{at}ucsf.edu

This article has been cited by other articles:

				S. Carnicella, V. Kharazia, J. Jeanblanc, P. H. Janak, and D. Ron GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse PNAS, June 10, 2008; 105(23): 8114 - 8119. [Abstract] [Full Text] [PDF]

				R. Jurd, C. Thornton, J. Wang, K. Luong, K. Phamluong, V. Kharazia, S. L. Gibb, and D. Ron Mind Bomb-2 Is an E3 Ligase That Ubiquitinates the N-Methyl-D-aspartate Receptor NR2B Subunit in a Phosphorylation-dependent Manner J. Biol. Chem., January 4, 2008; 283(1): 301 - 310. [Abstract] [Full Text] [PDF]

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