Cyclic adenosine monophosphate-independent tyrosine phosphorylation of NR2B mediates cocaine-induced extracellular signal-regulated kinase activation.
BACKGROUND
Activation of the extracellular signal-regulated kinase (ERK) in the striatum is crucial for long-term behavioral alterations induced by drugs of abuse. In response to cocaine, ERK phosphorylation (i.e., activation) is restricted to medium-sized spiny neurons expressing dopamine D1 receptor (D1R) and depends on a concomitant stimulation of D1R and glutamate N-methyl-D-aspartate receptor (NMDAR). However, the mechanisms responsible for this activation, especially the respective contribution of D1R and NMDAR, remain unknown.


METHODS
We studied striatal neurons in culture stimulated with D1R agonist and/or glutamate and wild-type or genetically modified mice treated with cocaine. Biochemical, immunohistochemical, and imaging studies were performed. Mice were also subjected to behavioral experiments.


RESULTS
Stimulation of D1R cannot activate ERK by itself but potentiates glutamate-mediated calcium influx through NMDAR that is responsible for ERK activation. Potentiation of NMDAR by D1R depends on a cyclic adenosine monophosphate-independent signaling pathway, which involves tyrosine phosphorylation of the NR2B subunit of NMDAR by Src family kinases. We also demonstrate that the D1R/Src family kinases/NR2B pathway is responsible for ERK activation by cocaine in vivo. Inhibition of this pathway abrogates cocaine-induced locomotor sensitization and conditioned place preference.


CONCLUSIONS
Our results show that potentiation of NR2B-containing NMDAR by D1R is necessary and sufficient to trigger cocaine-induced ERK activation. They highlight a new cyclic adenosine monophosphate-independent pathway responsible for the integration of dopamine and glutamate signals by the ERK cascade in the striatum and for long-term behavioral alterations induced by cocaine.
Centre National de la Recherché Scientifique Unité Mixte de Recherche, Paris, France.
Vincent
V
Pascoli
Antoine
A
Besnard
Denis
D
Hervé
Christiane
C
Pagès
Nicolas
N
Heck
Jean-Antoine
JA
Girault
Jocelyne
J
Caboche
Peter
P
Vanhoutte
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004347:Drug Interactions; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018698:Glutamic Acid / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D010766:Phosphorylation / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D018698:Glutamic Acid; D014443:Tyrosine; D000242:Cyclic AMP; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D003042:Cocaine; D002118:Calcium