Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling.
Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling.
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DOI：
10.1371/journal.pone.0001187
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发表时间：
2007-11-14
期刊：
影响因子：
3.7
通讯作者：
Pablo J
中科院分区：
文献类型：
--
作者：
Mash DC;ffrench-Mullen J;Adi N;Qin Y;Buck A;Pablo J
可卡因滥用对大脑结构和功能的慢性影响被认为是大多数成瘾者无法保持戒断的原因。防止复发的部分困难在于强烈的欣快感或可卡因“冲动”的持续记忆。大多数滥用的药物和酒精都会引起有助于情感和认知的大脑通路的神经可塑性变化。这些变化可能是暴露于可卡因后突触连接的巩固和结构重构的原因。适应性海马可塑性可能与慢性可卡因滥用的特定基因表达模式有关。在这里，我们比较了可卡因成瘾者和年龄匹配的无药物对照组的人类海马体中的基因表达谱。可卡因滥用者有151个基因转录本上调，而91个基因转录本下调。在可卡因调节的转录物列表中，人类海马体中的RECK（FC = 2.0; p<0.05）位居榜首。 RECK是一种膜锚定的MMP抑制剂，参与细胞外基质完整性和血管生成的协调调节。与RECK表达升高一致，可卡因滥用者海马中活性MMP 9蛋白水平降低。途径分析鉴定了可卡因调节的其他基因，其编码参与细胞基质和突触连接重塑以及抑制血管增殖的蛋白质（PCDH 8、LAMB 1、ITGB 6、CTGF和EphB 4）。在人类海马中观察到的微阵列表型鉴定了RECK和其他区域特异性基因，这些基因可能促进重复可卡因滥用的长期结构变化。海马细胞外基质重塑可能是慢性滥用的持续影响，导致可卡因成瘾的强迫性和复发性。
The chronic effects of cocaine abuse on brain structure and function are blamed for the inability of most addicts to remain abstinent. Part of the difficulty in preventing relapse is the persisting memory of the intense euphoria or cocaine “rush”. Most abused drugs and alcohol induce neuroplastic changes in brain pathways subserving emotion and cognition. Such changes may account for the consolidation and structural reconfiguration of synaptic connections with exposure to cocaine. Adaptive hippocampal plasticity could be related to specific patterns of gene expression with chronic cocaine abuse. Here, we compare gene expression profiles in the human hippocampus from cocaine addicts and age-matched drug-free control subjects. Cocaine abusers had 151 gene transcripts upregulated, while 91 gene transcripts were downregulated. Topping the list of cocaine-regulated transcripts was RECK in the human hippocampus (FC = 2.0; p<0.05). RECK is a membrane-anchored MMP inhibitor that is implicated in the coordinated regulation of extracellular matrix integrity and angiogenesis. In keeping with elevated RECK expression, active MMP9 protein levels were decreased in the hippocampus from cocaine abusers. Pathway analysis identified other genes regulated by cocaine that code for proteins involved in the remodeling of the cytomatrix and synaptic connections and the inhibition of blood vessel proliferation (PCDH8, LAMB1, ITGB6, CTGF and EphB4). The observed microarray phenotype in the human hippocampus identified RECK and other region-specific genes that may promote long-lasting structural changes with repeated cocaine abuse. Extracellular matrix remodeling in the hippocampus may be a persisting effect of chronic abuse that contributes to the compulsive and relapsing nature of cocaine addiction.
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影响因子：
56.9
作者：
Mellor, J;Nicoll, RA;Schmitz, D
通讯作者：
Schmitz, D
影响因子：
11.4
作者：
Erber, R;Eichelsbacher, U;Vajkoczy, P
通讯作者：
Vajkoczy, P
影响因子：
9.8
作者：
Chang HY;Sneddon JB;Alizadeh AA;Sood R;West RB;Montgomery K;Chi JT;van de Rijn M;Botstein D;Brown PO
通讯作者：
Brown PO
影响因子：
2.5
作者：
Magee, JC;Carruth, M
通讯作者：
Carruth, M
DOI：
10.1002/ajmg.b.30436
发表时间：
2006-12-05
影响因子：
2.8
作者：
Liu, Qing-Rong;Drgon, Tomas;Uhl, George R.
通讯作者：
Uhl, George R.