title: Chronic cocaine self-administration modulates ERK1/2 and CREB responses to dopamine receptor agonists in striatal slices.
abstract: Cocaine abuse leads to adaptations in brain reward circuits, where dopaminergic neurotransmission is a fundamental component. We hypothesized that chronic cocaine self-administration could influence dopamine D1 and D2 receptor activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. Male Sprague Dawley rats were exposed to cocaine self-administration for 6-11 weeks. Brains from sham controls and cocaine rats were extracted 1 day after the last session, and slices obtained from the striatum and nucleus accumbens (NAc) were incubated in vitro with or without the D1R agonist SKF38393 or the D2R agonist quinpirole. We found that cocaine self-administration led to a reduction in the capacity of D1R to activate ERK1/2 phosphorylation as compared with control rats. Cocaine self-administration also reduced D1R agonist-induced CREB phosphorylation in striatal slices, suggesting a downregulation of D1R signaling. D2R-induced ERK1/2 phosphorylation appeared blunted in striatal slices from cocaine rats. In contrast, surprisingly, cocaine self-administration strongly potentiated D2R agonist-induced CREB phosphorylation selectively in the NAc portion of the slices. Altered agonist-induced signaling was independent of total ERK1/2 and CREB expression. Our finding that selected cellular D2R responses to CREB were strengthened by cocaine self-administration could be relevant to understand how dopaminergic receptors participate in cocaine-induced behaviors.
authors.affiliation: Neuroscience Institute, Department of Biochemistry and Molecular Biology, School of Medicine, Universitat Autònoma de Barcelona, Spain.
authors.forename: Hanne M
authors.initials: HM
authors.lastname: Hoffmann
authors.forename: Roser
authors.initials: R
authors.lastname: Nadal
authors.forename: Michel
authors.initials: M
authors.lastname: Vignes
authors.forename: Jordi
authors.initials: J
authors.lastname: Ortiz
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D003042:Cocaine