Mash Deborah C, ffrench-Mullen Jarlath, Adi Nikhil, Qin Yujing, Buck Andrew, Pablo John
Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
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.
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状态的原因。预防复吸的部分困难在于对强烈欣快感或可卡因“冲动”的持久记忆。大多数滥用的药物和酒精会在服务于情绪和认知的大脑通路中引起神经可塑性变化。这种变化可能解释了接触可卡因后突触连接的巩固和结构重构。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毒品对照受试者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。人类海马体中受可卡因调节的转录本中排名第一的是RECK（倍数变化=2.0；p<0.05）。RECK是一种膜锚定的基质金属蛋白酶抑制剂，与细胞外基质完整性和血管生成的协调调节有关。与RECK表达升高一致，可卡因滥用者海马体中的活性基质金属蛋白酶9蛋白水平降低。通路分析确定了其他受可卡因调节的基因，这些基因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（原钙黏蛋白8、层粘连蛋白β1、整合素β6、结缔组织生长因子和 EphB4）。在人类海马体中观察到的微阵列表型确定了RECK和其他区域特异性基因，这些基因可能随着反复滥用可卡因促进持久的结构变化。海马体中的细胞外基质重塑可能是慢性滥用的持续影响，这导致了可卡因成瘾的强迫性和复发性。
