Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior.
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.
Wang
Jun
J
Ernest Gallo Research Center, Emeryville, California 94608, USA.
Carnicella
Sebastien
S
Phamluong
Khanhky
K
Jeanblanc
Jerome
J
Ronesi
Jennifer A
JA
Chaudhri
Nadia
N
Janak
Patricia H
PH
Lovinger
David M
DM
Ron
Dorit
D
D000428:Alcohol Drinking / Q000503:physiopathology* / Q000523:psychology; D000818:Animals; D016739:Behavior, Addictive / Q000503:physiopathology*; D003216:Conditioning, Operant; D003342:Corpus Striatum / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D012646:Self Administration; D012932:Social Facilitation
C121001:NR2B NMDA receptor; D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn