title: Cocaine activates Rac1 to control structural and behavioral plasticity in caudate putamen.
abstract: Repeated exposure to cocaine was previously found to cause sensitized behavioral responses and structural remodeling on medium spiny neurons of the nucleus accumbens (NAc) and caudate putamen (CPu). Rac1 has emerged as a key integrator of environmental cues that regulates dendritic cytoskeletons. In this study, we investigated the role of Rac1 in cocaine-induced dendritic and behavioral plasticity in the CPu. We found that Rac1 activation was reduced in the NAc but increased in the CPu following repeated cocaine treatment. Inhibition of Rac1 activity by a Rac1-specific inhibitor NSC23766, overexpression of a dominant negative mutant of Rac1 (T17N-Rac1) or local knockout of Rac1 attenuated the cocaine-induced increase in dendrites and spine density in the CPu, whereas overexpression of a constitutively active Rac1 exert the opposite effect. Moreover, NSC23766 reversed the increased number of asymmetric spine synapses in the CPu following chronic cocaine exposure. Downregulation of Rac1 activity likewise attenuates behavioral reward responses to cocaine exposure, with activation of Rac1 producing the opposite effect. Thus, Rac1 signaling is differentially regulated in the NAc and CPu after repeated cocaine treatment, and induction of Rac1 activation in the CPu is important for cocaine exposure-induced dendritic remodeling and behavioral plasticity.
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China; Department of Histology and Embryology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Histology and Embryology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Minjuan
authors.initials: M
authors.lastname: Xie
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Xue
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Elderly Health Services Research Center, Southern Medical University, Guangzhou 510515, China.
authors.forename: Nuyun
authors.initials: N
authors.lastname: Liu
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, OH, USA.
authors.forename: Fukun
authors.initials: F
authors.lastname: Guo
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, OH, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Southern Medical University-University of Manitoba Geriatric Medicine Joint Laboratory, Guangzhou 510515, China.
authors.forename: Jiming
authors.initials: J
authors.lastname: Kong
authors.affiliation: Department of Histology and Embryology, Southern Medical University, Guangzhou 510515, China. Electronic address: zlilyzh@126.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China; Elderly Health Services Research Center, Southern Medical University, Guangzhou 510515, China; Southern Medical University-University of Manitoba Geriatric Medicine Joint Laboratory, Guangzhou 510515, China. Electronic address: zlulu70@126.com.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
mesh_terms: D017109:Akathisia, Drug-Induced / Q000503:physiopathology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002491:Central Nervous System Agents / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003712:Dendrites / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D008297:Male; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011699:Putamen / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D002491:Central Nervous System Agents; D018765:Dopamine Uptake Inhibitors; C487513:NSC 23766; D009479:Neuropeptides; D011743:Pyrimidines; C484602:Rac1 protein, mouse; D020830:rac1 GTP-Binding Protein; D003042:Cocaine
keywords: Behavioral plasticity; Caudate putamen (CPu); Cocaine; Dendritic plasticity; Rac1