近日,，國(guó)際學(xué)術(shù)期刊《神經(jīng)科學(xué)雜志》（The Journal of Neuroscience）發(fā)表了中科院上海藥物研究所劉景根課題組和昆明動(dòng)物所徐林課題組合作的最新研究成果,。該工作發(fā)現(xiàn)了長(zhǎng)期使用阿片類物質(zhì)嗎啡引起腦記憶和認(rèn)知功能障礙的新機(jī)制。
腦認(rèn)知功能障礙是阿片類物質(zhì)的一個(gè)重要有害作用,。越來越多的研究表明，認(rèn)知功能障礙可能與成癮者強(qiáng)迫性攝藥和戒斷后復(fù)吸有關(guān),。但目前對(duì)阿片類物質(zhì)損害腦認(rèn)知功能的機(jī)制仍有待進(jìn)一步闡明,。這項(xiàng)研究工作發(fā)現(xiàn)，慢性給予小鼠嗎啡可通過增加海馬細(xì)胞外腺苷濃度,，激活腺苷A1受體抑制海馬CA1區(qū)突觸可塑性（LTP）和削弱認(rèn)知功能,。
研究工作進(jìn)一步發(fā)現(xiàn),，細(xì)胞外腺苷濃度增加是由于腺苷轉(zhuǎn)運(yùn)體功能降低所引起。慢性嗎啡處理可通過PKC依賴和不依賴兩種機(jī)制削弱轉(zhuǎn)運(yùn)體功能,。PKCα/β活性下降與停藥后短期出現(xiàn)的轉(zhuǎn)運(yùn)體功能降低有關(guān),。研究工作還發(fā)現(xiàn)，認(rèn)知功能障礙是由慢性嗎啡處理本身所引起,，而與撤藥出現(xiàn)的戒斷反應(yīng)無關(guān),。研究工作為了解阿片類物質(zhì)引起腦認(rèn)知功能障礙的機(jī)制提供了新的認(rèn)知，對(duì)闡明阿片類物質(zhì)依賴的機(jī)制有一定意義,。
該工作主要由盧剛和周啟心博士完成,，研究工作得到上海藥物所代謝中心鐘大放和陳笑艷研究員的大力幫助。研究工作得到了國(guó)家杰出青年基金,，科技部973計(jì)劃和中科院重要方向項(xiàng)目的資助,。(生物谷Bioon.com)
腦認(rèn)知障礙研究獲新進(jìn)展
Neuron：神經(jīng)元編碼理論受到質(zhì)疑 大腦認(rèn)知之謎解開
生物谷推薦原文出處：
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.
