title: Cocaine-induced synaptic structural modification is differentially regulated by dopamine D1 and D3 receptors-mediated signaling pathways.
abstract: Synaptic plasticity plays a critical role in cocaine addiction. The dopamine D1 and D3 receptors differentially regulate the cocaine-induced gene expression, structural remodeling and behavioral response. However, how these two receptors coordinately mediate the ultra-structural changes of synapses after cocaine exposure and whether these changes are behaviorally relevant are still not clear. Here, using quantitative electron microscopy, we show that D1 and D3 receptors have distinct roles in regulating cocaine-induced ultra-structural changes of synapses in the nucleus accumbens and caudoputamen. Pre-treatment of cocaine-treated mice with D3 receptor antagonist NGB2904 resulted in an increase in the ratio of total and asymmetric synapse to neuron and in the length of postsynaptic densities, compared with cocaine treatment alone. In contrast, pre-treatment of cocaine-treated mice with D1 receptor antagonist SCH23390 caused a reduction in synapse-to-neuron ratio and in postsynaptic densities length. Similarly, NGB2904 and SCH23390 showed opposite/differential effects on cocaine-induced structural plasticity, conditioned place preference and locomotor activity and signaling activation, including the activation of ERK, CREB and NR1 and the expression of c-fos and Cdk5. Therefore, we provide direct electron microscopy evidence that dopamine D1 and D3 receptors reciprocally regulate the ultra-structural changes of synapses following chronic exposure to cocaine. In addition, our data suggest that D1 and D3 receptors may regulate cocaine-induced ultra-structural changes and behavior responses by impact on structural plasticity and signaling transduction.
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, China.|Key Laboratory of Construction and Detection in Tissue Engineering of Guangdong Province, Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Huang
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, China.
authors.forename: Kangrong
authors.initials: K
authors.lastname: Lu
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, China.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, China.
authors.forename: Genghong
authors.initials: G
authors.lastname: Tu
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, China.
authors.forename: Mengjuan
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ying
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, China.
authors.forename: Jinlan
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Elderly Health Services Research Center, Southern Medical University, China.
authors.forename: N
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: Key Laboratory of Construction and Detection in Tissue Engineering of Guangdong Province, Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Functional Proteomics of Guangdong Province, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, China.|Elderly Health Services Research Center, Southern Medical University, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D003042:Cocaine
keywords: CPP; Cocaine; dopamine receptors; electron microscope; locomotor activity; stereology; structural plasticity