脑内LTCCs在药物成瘾形成过程中的调控机制  

The mechanism of intracerebral L-type voltage dependent calcium channels in drug addiction

作　　者：金书博 沈芳[1] 段颖[1,2] 李鸣 隋南[1] 

机构地区：[1]中国科学院心理研究所、中国科学院心理健康重点实验室,北京100101 [2]中国科学院大学,北京100049 [3]Department of Psychology,University of Nebraska-Lincoln,Lincoln NE 68588,USA

出　　处：《科学通报》2016年第11期1173-1180,共8页Chinese Science Bulletin

基　　金：国家重点基础研究发展计划(2015CB553501);国家自然科学基金重大研究计划培育项目(91332115),国家自然科学基金(31170988,31500893,31428008)资助

摘　　要：药物成瘾伴随中枢神经系统内钙离子通道数目及开放状态的适应性改变.大量证据表明,L型电压依赖性钙通道(LTCCs)可通过调节神经递质的释放、神经兴奋性、基因的转录及突触可塑性等过程调控成瘾行为.最新的研究还表明,LTCCs的不同亚型Ca_v1.2和Ca_v1.3对药物成瘾的调控分别依赖于D1及D2受体,且具有脑区及分子机制特异性.并且,Cav1.3的a亚基能够与内质网钙通道蛋白(Ry R2)的N末端氨基酸相互结合,促进胞内钙库Ca^(2+)的释放.此外,骨架蛋白激酶A锚定蛋白79/150(AKAP79/150)可将LTCCs锚定在突触膜上,从而调控成瘾药物诱导的突触可塑性改变.本文将重点讨论LTCCs在药物成瘾中发挥的调控作用及其潜在的细胞及分子机制.Changes of intracellular calcium are the fundament of cell physiological function and the key factor in intracellular signal transduction and gene expression. Recently more studies have been focusing on the relationship between voltage dependent calcium channels（VDCCs） and drug addiction. A great deal of evidence suggests that L-type VDCCs（LTCCs）, which are activated by membrane depolarization, play an important role in drug addiction by affecting the release of neurotransmitters, excitability of neurons, gene transcription and synaptic plasticity. LTCCs are divided into four subtypes： Ca_v1.1, Ca_v1.2, Ca_v1.3 and Ca_v1.4, according to the conduction of single channel and sensitivity to calcium antagonists and agonists. Among them Cav1.2 and Ca_v1.3 are mainly expressed in the central nervous system. It is reported that the increasing of intracellular calcium induced by LTCCs is crucial in physical dependence and withdrawal symptoms of addictive drugs such as morphine. In addition, the enhancement of c AMP-response element binding protein（CREB） and ryanodine receptor 2（Ry R2） induced by LTCCs on endoplasmic reticulum（ER） stimulate the release of calcium in cytoplasm, leading to a long-term increase in intracellular calcium. This relation might underlie the dependence and tolerance of nicotine. Moreover, it is reported that LTCCs also take part in nonsomatic signs of drug withdrawal. For example, intraperitoneal injection of LTCCs antagonists can reduce nonsomatic withdrawal symptoms in chronic nicotine-dependent rats, like anxiety, memory impartment and depression-like effects. Furthermore, recent researches also find that Ca_v1.2 and Ca_v1.3 play an important role in the acquisition and expression of cocaine-induced behavioral sensitization through different molecular mechanisms in specific brain regions. For instance, Cav_1.3 in the ventral tegmental area（VTA） affects the development of cocaine sensitization by activating extracellular regulated protein kinases 2（ERK2）; While in t

关 键 词：LTCCs 成瘾记忆 突触可塑性 Cav1.2 Cav1.3 

分 类 号：R749.6[医药卫生—神经病学与精神病学]