کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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4178932 | 1276522 | 2011 | 10 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Cyclic Adenosine Monophosphate–Independent Tyrosine Phosphorylation of NR2B Mediates Cocaine-Induced Extracellular Signal-Regulated Kinase Activation Cyclic Adenosine Monophosphate–Independent Tyrosine Phosphorylation of NR2B Mediates Cocaine-Induced Extracellular Signal-Regulated Kinase Activation](/preview/png/4178932.png)
BackgroundActivation 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.MethodsWe 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.ResultsStimulation 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.ConclusionsOur 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.
Journal: Biological Psychiatry - Volume 69, Issue 3, 1 February 2011, Pages 218–227