Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action

doi:10.1371/journal.pone.0051910

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	Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action
	Zhang, Chun-Lei 2,3; Feng, Ze-Jun 2,3; Liu, Yue 2,3; Ji, Xiao-Hua 2,3; Peng, Ji-Yun 2,3; Zhang, Xue-Han 2,3; Zhen, Xue-Chu 1; Li, Bao-Ming 2,3,4
刊名	PLOS ONE
	2012-12-20
卷号	7 期号:12
ISSN号	1932-6203
DOI	10.1371/journal.pone.0051910
文献子类	Article
英文摘要	Methylphenidate (MPH), commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD). Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and alpha 2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V similar to VI pyramidal cells of the rat medial prefrontal cortex (PFC). To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by sigma 1 but not D1/5 and alpha 2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca2+ increase, but does not require PKA and extracellular Ca2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with sigma 1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via sigma 1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.
资助项目	Ministry of Science and Technology of China[2006CB500807] ; Ministry of Science and Technology of China[2011CBA00406] ; National Natural Science Foundation of China[30700218] ; National Natural Science Foundation of China[30821002] ; National Natural Science Foundation of China[30990263]
WOS关键词	METHYL-D-ASPARTATE ; PROTEIN-KINASE-C ; DEFICIT-HYPERACTIVITY DISORDER ; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ; INDUCED NEURONAL ACTIVATION ; CA(3) DORSAL HIPPOCAMPUS ; SPATIAL WORKING-MEMORY ; LONG-TERM POTENTIATION ; FREELY BEHAVING RATS ; NEUROPSYCHIATRIC DISORDERS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000312794500064
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277841]
专题	药理学第二研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Li, Bao-Ming
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Neuropharmacol Lab, State Key Lab Drug Res, Shanghai 200031, Peoples R China 2.Fudan Univ, Inst Neurobiol, Shanghai 200433, Peoples R China; 3.Fudan Univ, State Key Lab Med Neurobiol, Inst Brain Sci, Shanghai 200433, Peoples R China; 4.Nanchang Univ, Ctr Neuropsychiat Disorders, Inst Life Sci, Nanchang, Peoples R China;
推荐引用方式 GB/T 7714	Zhang, Chun-Lei,Feng, Ze-Jun,Liu, Yue,et al. Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action[J]. PLOS ONE,2012,7(12).
APA	Zhang, Chun-Lei.,Feng, Ze-Jun.,Liu, Yue.,Ji, Xiao-Hua.,Peng, Ji-Yun.,...&Li, Bao-Ming.(2012).Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action.PLOS ONE,7(12).
MLA	Zhang, Chun-Lei,et al."Methylphenidate Enhances NMDA-Receptor Response in Medial Prefrontal Cortex via Sigma-1 Receptor: A Novel Mechanism for Methylphenidate Action".PLOS ONE 7.12(2012).