Extracellular signal-regulated protein kinases 1 and 2 activation by addictive drugs: a signal toward pathological adaptation.
Addiction is a chronic and relapsing psychiatric disorder that is thought to occur in vulnerable individuals. Synaptic plasticity evoked by drugs of abuse in the so-called neuronal circuits of reward has been proposed to underlie behavioral adaptations that characterize addiction. By increasing dopamine in the striatum, addictive drugs alter the balance of dopamine and glutamate signals converging onto striatal medium-sized spiny neurons (MSNs) and activate intracellular events involved in long-term behavioral alterations. Our laboratory contributed to the identification of salient molecular changes induced by administration of addictive drugs to rodents. We pioneered the observation that a common feature of addictive drugs is to activate, by a double tyrosine/threonine phosphorylation, the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the striatum, which control a plethora of substrates, some of them being critically involved in cocaine-mediated molecular and behavioral adaptations. Herein, we review how the interplay between dopamine and glutamate signaling controls cocaine-induced ERK1/2 activation in MSNs. We emphasize the key role of N-methyl-D-aspartate receptor potentiation by D1 receptor to trigger ERK1/2 activation and its subsequent nuclear translocation where it modulates both epigenetic and genetic processes engaged by cocaine. We discuss how cocaine-induced long-term synaptic and structural plasticity of MSNs, as well as behavioral adaptations, are influenced by ERK1/2-controlled targets. We conclude that a better knowledge of molecular mechanisms underlying ERK1/2 activation by drugs of abuse and/or its role in long-term neuronal plasticity in the striatum may provide a new route for therapeutic treatment in addiction.
Department of Basic Neurosciences, University Medical Center, University of Geneva, Geneva, Switzerland.
Vincent
V
Pascoli
Institut de Biologie Paris, Seine, CNRS/UMR8246-INSERM/UMR-S1130, Université Pierre et Marie Curie.
Emma
E
Cahill
Department of Adult Psychiatry, L׳Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Saint-Louis, Lariboisière, Fernand-Widal Sites; Unité de Formation et de Recherche de Médecine, Université Denis Diderot; Variability of the Response to Psychotropic Drugs, Institut National de la Santé et de la; Recherche Médicale, Paris; and Fondation FondaMental, Créteil, France.
Frank
F
Bellivier
Institut de Biologie Paris, Seine, CNRS/UMR8246-INSERM/UMR-S1130, Université Pierre et Marie Curie.
Jocelyne
J
Caboche
Institut de Biologie Paris, Seine, CNRS/UMR8246-INSERM/UMR-S1130, Université Pierre et Marie Curie. Electronic address: peter.vanhoutte@snv.jussieu.fr.
Peter
P
Vanhoutte
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D018765:Dopamine Uptake Inhibitors; D018698:Glutamic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003042:Cocaine; D004298:Dopamine
Addiction; cocaine; dopamine; extracellular signal-regulated kinases 1 and 2 (ERK1/2); glutamate; synaptic plasticity