title: Protein kinase D1-dependent phosphorylation of dopamine D1 receptor regulates cocaine-induced behavioral responses.
abstract: The dopamine (DA) D1 receptor (D1R) is critically involved in reward and drug addiction. Phosphorylation-mediated desensitization or internalization of D1R has been extensively investigated. However, the potential for upregulation of D1R function through phosphorylation remains to be determined. Here we report that acute cocaine exposure induces protein kinase D1 (PKD1) activation in the rat striatum, and knockdown of PKD1 in the rat dorsal striatum attenuates cocaine-induced locomotor hyperactivity. Moreover, PKD1-mediated phosphorylation of serine 421 (S421) of D1R promotes surface localization of D1R and enhances downstream extracellular signal-regulated kinase signaling in D1R-transfected HEK 293 cells. Importantly, injection of the peptide Tat-S421, an engineered Tat fusion-peptide targeting S421 (Tat-S421), into the rat dorsal striatum inhibits cocaine-induced locomotor hyperactivity and injection of Tat-S421 into the rat hippocampus or the shell of the nucleus accumbens (NAc) also inhibits cocaine-induced conditioned place preference (CPP). However, injection of Tat-S421 into the rat NAc shell does not establish CPP by itself and injection of Tat-S421 into the hippocampus does not influence spatial learning and memory. Thus, targeting S421 of D1R represents a promising strategy for the development of pharmacotherapeutic treatments for drug addiction and other disorders that result from DA imbalances.
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology, The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission, Peking University Health Science Center, Beijing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology, The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission, Peking University Health Science Center, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Su
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology, The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission, Peking University Health Science Center, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology, The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission, Peking University Health Science Center, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology, The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission, Peking University Health Science Center, Beijing, China.
authors.forename: Baoming
authors.initials: B
authors.lastname: Xing
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology, The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission, Peking University Health Science Center, Beijing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Kang
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology, The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission, Peking University Health Science Center, Beijing, China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Li
authors.affiliation: 1] Neuroscience Research Institute and Department of Neurobiology, The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission, Peking University Health Science Center, Beijing, China [2] PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D017109:Akathisia, Drug-Induced / Q000378:metabolism*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D014162:Transfection
chemical_list: D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; C089212:protein kinase D; D011493:Protein Kinase C; D003042:Cocaine