近日，国际学术期刊《神经科学杂志》（The Journal of Neuroscience）发表了中科院上海药物研究所刘景根课题组和昆明动物所徐林课题组合作的最新研究成果。该工作发现了长期使用阿片类物质吗啡引起脑记忆和认知功能障碍的新机制。
脑认知功能障碍是阿片类物质的一个重要有害作用。越来越多的研究表明，认知功能障碍可能与成瘾者强迫性摄药和戒断后复吸有关。但目前对阿片类物质损害脑认知功能的机制仍有待进一步阐明。这项研究工作发现，慢性给予小鼠吗啡可通过增加海马细胞外腺苷浓度，激活腺苷A1受体抑制海马CA1区突触可塑性（LTP）和削弱认知功能。
研究工作进一步发现，细胞外腺苷浓度增加是由于腺苷转运体功能降低所引起。慢性吗啡处理可通过PKC依赖和不依赖两种机制削弱转运体功能。PKCα/β活性下降与停药后短期出现的转运体功能降低有关。研究工作还发现，认知功能障碍是由慢性吗啡处理本身所引起，而与撤药出现的戒断反应无关。研究工作为了解阿片类物质引起脑认知功能障碍的机制提供了新的认知，对阐明阿片类物质依赖的机制有一定意义。
该工作主要由卢刚和周启心博士完成，研究工作得到上海药物所代谢中心钟大放和陈笑艳研究员的大力帮助。研究工作得到了国家杰出青年基金，科技部973计划和中科院重要方向项目的资助。(生物谷Bioon.com)
脑认知障碍研究获新进展
Neuron：神经元编码理论受到质疑 大脑认知之谜解开
生物谷推荐原文出处：
The Journal of Neuroscience, April 7, 2010, 30(14):5058-5070; doi:10.1523/JNEUROSCI.0148-10.2010
Chronic Morphine Treatment Impaired Hippocampal Long-Term Potentiation and Spatial Memory via Accumulation of Extracellular Adenosine Acting on Adenosine A1 Receptors
Gang Lu,1 * Qi-Xin Zhou,2 * Shuo Kang,1 Qing-Lin Li,3 Liang-Cai Zhao,3 Jia-Dong Chen,4 Jian-Feng Sun,1 Jun Cao,2 Yu-Jun Wang,1 Jie Chen,1 Xiao-Yan Chen,1 Da-Fang Zhong,1 Zhi-Qiang Chi,1 Lin Xu,2 and Jing-Gen Liu1
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute For Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China, 2Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China, 3Anhui University of Traditional Chinese Medicine, Hefei 230032, China, and 4State Key Laboratory of Neuroscience, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China
Chronic exposure to opiates impairs hippocampal long-term potentiation (LTP) and spatial memory, but the underlying mechanisms remain to be elucidated. Given the well known effects of adenosine, an important neuromodulator, on hippocampal neuronal excitability and synaptic plasticity, we investigated the potential effect of changes in adenosine concentrations on chronic morphine treatment-induced impairment of hippocampal CA1 LTP and spatial memory. We found that chronic treatment in mice with either increasing doses (20–100 mg/kg) of morphine for 7 d or equal daily dose (20 mg/kg) of morphine for 12 d led to a significant increase of hippocampal extracellular adenosine concentrations. Importantly, we found that accumulated adenosine contributed to the inhibition of the hippocampal CA1 LTP and impairment of spatial memory retrieval measured in the Morris water maze. Adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine significantly reversed chronic morphine-induced impairment of hippocampal CA1 LTP and spatial memory. Likewise, adenosine deaminase, which converts adenosine into the inactive metabolite inosine, restored impaired hippocampal CA1 LTP. We further found that adenosine accumulation was attributable to the alteration of adenosine uptake but not adenosine metabolisms. Bidirectional nucleoside transporters (ENT2) appeared to play a key role in the reduction of adenosine uptake. Changes in PKC-/β activity were correlated with the attenuation of the ENT2 function in the short-term (2 h) but not in the long-term (7 d) period after the termination of morphine treatment. This study reveals a potential mechanism by which chronic exposure to morphine leads to impairment of both hippocampal LTP and spatial memory.
