title: Dissociative role for dorsal hippocampus in mediating heroin self-administration and relapse through CDK5 and RhoB signaling revealed by proteomic analysis.
abstract: Addiction is characterized by drug craving, compulsive drug taking and relapse, which is attributed to aberrant neuroadaptation in brain regions implicated in drug addiction, induced by changes in gene and protein expression in these regions after chronic drug exposure. Accumulating evidence suggests that the dorsal hippocampus (DH) plays an important role in mediating drug-seeking and drug-taking behavior and relapse. However, the molecular mechanisms underlying these effects of the DH are unclear. In the present study, we employed a label-free quantitative proteomic approach to analyze the proteins altered in the DH of heroin self-administering rats. A total of 4015 proteins were quantified with high confidence, and 361 proteins showed significant differences compared with the saline control group. Among them, cyclin-dependent kinase 5 (CDK5) and ras homolog family member B (RhoB) were up-regulated in rats with a history of extended access to heroin. Functionally, inhibition of CDK5 in the DH enhanced heroin self-administration, indicating that CDK5 signaling in the DH acts as a homeostatic compensatory mechanism to limit heroin-taking behavior, whereas blockade of the Rho-Rho kinase (ROCK) pathway attenuated context-induced heroin relapse, indicating that RhoB signaling in the DH is required for the retrieval (recall) of addiction memory. Our findings suggest that manipulation of CDK5 signaling in the DH may be essential in determining vulnerability to opiate taking, whereas manipulation of RhoB signaling in the DH may be essential in determining vulnerability to relapse. Overall, the present study suggests that the DH can exert dissociative effects on heroin addiction through CDK5 and RhoB signaling.
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhong-Guo
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Weisheng
authors.initials: W
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Geng
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Chen-Ling
authors.initials: CL
authors.lastname: Gan
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jing-Rui
authors.initials: JR
authors.lastname: Chai
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing, China.
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, China.|SIMMUOMICS Laboratory, Joint Research Laboratory of Translational "OMICS" between Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China and University of Ottawa, Canada.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica and Collaborative Innovation Center for Brain Science, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jing-Gen
authors.initials: JG
authors.lastname: Liu
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D058999:Drug-Seeking Behavior / Q000187:drug effects; D003932:Heroin / Q000008:administration & dosage / Q000494:pharmacology*; D006556:Heroin Dependence / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology; D040901:Proteomics / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D012646:Self Administration; D015398:Signal Transduction / Q000187:drug effects*; D020743:rhoB GTP-Binding Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D009294:Narcotics; D003932:Heroin; D051360:Cyclin-Dependent Kinase 5; D020743:rhoB GTP-Binding Protein
keywords: CDK5; RhoB; dorsal hippocampus; heroin self-administration; label-free proteomic analysis; the centrifugal proteomic reactor