Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior

J Neurosci. 2007 Mar 28;27(13):3593-602. doi: 10.1523/JNEUROSCI.4749-06.2007.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / physiopathology*
  • Alcohol Drinking / psychology
  • Animals
  • Behavior, Addictive / physiopathology*
  • Conditioning, Operant
  • Corpus Striatum / drug effects*
  • Ethanol / pharmacology*
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuronal Plasticity / drug effects
  • Neurotransmitter Agents / metabolism
  • Nucleus Accumbens / drug effects*
  • Patch-Clamp Techniques
  • Phosphorylation
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Rats
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Self Administration
  • Social Facilitation

Substances

  • NR2B NMDA receptor
  • Neurotransmitter Agents
  • Receptors, N-Methyl-D-Aspartate
  • Ethanol
  • Fyn protein, rat
  • Proto-Oncogene Proteins c-fyn