Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems.
Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems.
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DOI：
10.1016/j.nlm.2011.04.011
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发表时间：
2011-09
影响因子：
2.7
通讯作者：
Walker, Brendan M.
中科院分区：
文献类型：
--
作者：
Smith, Alexander W.;Nealey, Kathryn A.;Wright, John W.;Walker, Brendan M.
关键词：
酒精中毒和戒断与依赖性相关的重复循环诱导各种脑系统的神经适应。戒断引起的消极情绪状态可以通过酒精的消耗得到改善;一个被称为负强化的学习过程。因此，依赖性诱导的表型是乙醇自我给药逐步增加。基质金属蛋白酶（MMP）是降解细胞外基质以允许突触重组和可塑性的蛋白水解酶。为了检验以下假设：动物需要完整的MMP系统来了解乙醇的负面强化作用，并在乙醇依赖性急性戒断期间显示逐步增加的自我给药，训练雄性Wistar大鼠自我给药乙醇，然后将其分配至急性或慢性MMP抑制治疗组。慢性治疗组在一个月的乙醇依赖诱导期和随后的急性戒断期间发生的依赖诱导后自我给药阶段通过渗透性微型泵接受脑室内（ICV）输注广谱MMP抑制剂FN-439或人工脑脊液（aCSF）。急性治疗组仅在急性戒断期间依赖诱导后自我给药当天接受ICV FN-439或aCSF。结果表明，MMPs的抑制减弱了慢性和急性暴露条件下乙醇自我给药的增加。此外，一旦学习（即，可塑性）已经发生，MMP抑制对逐步增加的反应模式没有影响，并且一旦FN-439处理终止，先前经受MMP抑制的动物没有逐步增加，证明了操作性乙醇自我给药的正常逐步增加。因此，目前的数据表明，一个完整的MMP系统是需要的升级响应，发生在急性戒断依赖性动物，并暗示这种升级作为一个学习的反应。
Repeated cycles of ethanol intoxication and withdrawal associated with dependence induce neuroadaptations in a variety of brain systems. Withdrawal-induced negative emotional states can be ameliorated by ethanol consumption; a learned process termed negative reinforcement. Accordingly, a dependence-induced phenotype is escalated ethanol self-administration. Matrix metalloproteinases (MMPs) are proteolytic enzymes which degrade the extracellular matrix to allow for synaptic reorganization and plasticity. To test the hypothesis that an intact MMP system is required for animals to learn about the negative reinforcing effects of ethanol and display escalated self-administration during acute withdrawal when ethanol-dependent, male Wistar rats were trained to self-administer ethanol and then assigned to either acute or chronic MMP inhibition treatment groups. The chronic treatment group received intracerebroventricular (ICV) infusions of the broad spectrum MMP inhibitor FN-439 or artificial cerebrospinal fluid (aCSF) via osmotic minipumps during a one month ethanol dependence induction period and subsequent post-dependence induction self-administration sessions that occurred during acute withdrawal. The acute treatment group only received ICV FN-439 or aCSF on the day of self-administration sessions following dependence induction during acute withdrawal. The results showed that inhibition of MMPs attenuated escalated ethanol self-administration following chronic and acute exposure conditions. Furthermore, once learning (i.e., plasticity) had occurred, MMP inhibition had no impact on escalated response patterns and animals previously subjected to MMP inhibition that did not escalate evidenced normal escalations in operant ethanol self-administration once FN-439 treatments were terminated. Thus, the present data identified that an intact MMP system is required for the escalated responding that occurs during acute withdrawal in dependent animals and implicate such escalation as a learned response.
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