title: Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties.
abstract: A central feature of drugs of abuse is to induce gene expression in discrete brain structures that are critically involved in behavioral responses related to addictive processes. Although extracellular signal-regulated kinase (ERK) has been implicated in several neurobiological processes, including neuronal plasticity, its role in drug addiction remains poorly understood. This study was designed to analyze the activation of ERK by cocaine, its involvement in cocaine-induced early and long-term behavioral effects, as well as in gene expression. We show, by immunocytochemistry, that acute cocaine administration activates ERK throughout the striatum, rapidly but transiently. This activation was blocked when SCH 23390 [a specific dopamine (DA)-D1 antagonist] but not raclopride (a DA-D2 antagonist) was injected before cocaine. Glutamate receptors of NMDA subtypes also participated in ERK activation, as shown after injection of the NMDA receptor antagonist MK 801. The systemic injection of SL327, a selective inhibitor of the ERK kinase MEK, before cocaine, abolished the cocaine-induced ERK activation and decreased cocaine-induced hyperlocomotion, indicating a role of this pathway in events underlying early behavioral responses. Moreover, the rewarding effects of cocaine were abolished by SL327 in the place-conditioning paradigm. Because SL327 antagonized cocaine-induced c-fos expression and Elk-1 hyperphosphorylation, we suggest that the ERK intracellular signaling cascade is also involved in the prime burst of gene expression underlying long-term behavioral changes induced by cocaine. Altogether, these results reveal a new mechanism to explain behavioral responses of cocaine related to its addictive properties.
authors: Laboratoire de Neurochimie-Anatomie, Institut des Neurosciences, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7624, Université Pierre et Marie Curie, 75005 Paris, France.
authors: E
authors: E
authors: Valjent
authors: J C
authors: JC
authors: Corvol
authors: C
authors: C
authors: Pages
authors: M J
authors: MJ
authors: Besson
authors: R
authors: R
authors: Maldonado
authors: J
authors: J
authors: Caboche
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D004268:DNA-Binding Proteins; D065127:Dopamine D2 Receptor Antagonists; D004334:Drug Administration Schedule; D004336:Drug Antagonism; D004789:Enzyme Activation / Q000187:drug effects; D007150:Immunohistochemistry; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012201:Reward; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1
chemical_list: D004268:DNA-Binding Proteins; D065127:Dopamine D2 Receptor Antagonists; C494113:Elk1 protein, mouse; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D003042:Cocaine