Opposite regulation of cocaine-induced intracellular signaling and gene expression by dopamine D1 and D3 receptors.
Repeated exposure to cocaine induces persistent neuroadaptations that involve alterations in cellular signaling and gene expression mediated by dopamine (DA) receptors in the brain. Both dopamine D1 and D3 receptors mediate cocaine-induced behaviors and they are also coexpressed in the same neurons in the nucleus accumbens (NAc) and caudoputamen (CPu). We have investigated whether these two receptors coordinately regulate intracellular signaling and gene expression after acute and repeated cocaine administration. We found that extracellular signal-regulated kinase (ERK) activation and c-fos induction in the CPu following an acute cocaine administration is mediated by the D1 receptor and inhibited by the D3 receptor. ERK activation is necessary for acute cocaine-induced expression of fos family genes that include c-fos, fosB, and fra2. Furthermore, potential target genes of cAMP response element-binding (CREB) protein and/or AP-1 transcription complex, including dynorphin, neogenin, and synaptotagmin VII, are also oppositely regulated by D1 and D3 receptors after repeated cocaine injections. Lastly, such regulation requires proper ERK activation. These results suggest that D1 and D3 receptors oppositely regulate target gene expression by regulating ERK activation after cocaine administration.
Zhang
Jianhua
J
Department of Anesthesia and Critical Care, The University of Chicago, Chicago, IL 60637, USA. mxu@dacc.uchicago.edu
Xu
Ming
M
D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000502:physiology*; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D003042:Cocaine