Role of matrix metalloproteinases in the acquisition and reconsolidation of cocaine-induced conditioned place preference.
Role of matrix metalloproteinases in the acquisition and reconsolidation of cocaine-induced conditioned place preference.
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DOI：
10.1101/lm.476207
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发表时间：
2007-03-01
期刊：
影响因子：
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通讯作者：
Sorg, Barbara A
中科院分区：
文献类型：
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作者：
Brown, Travis E;Forquer, Melissa R;Sorg, Barbara A
持续的药物寻求/服用行为涉及记忆的巩固。随着每次药物使用，记忆可能被重新激活和重新巩固，以保持原始记忆。在再激活过程中，记忆可能变得不稳定，容易受到破坏;因此，参与可塑性的分子应该会影响获得和/或再巩固。最近，基质金属蛋白酶（MMPs）已被证明影响神经元的可塑性，可能是通过其调节细胞外基质（ECM）分子参与突触重组在学习过程中。我们假设，MMP活性的抑制将损害可卡因条件性位置偏爱（CPP）大鼠的收购和/或再巩固。脑室内（i. c. v.）在可卡因训练之前微量注射广谱MMP抑制剂FN-439抑制CPP的获得，并减弱可卡因引发的消退动物的恢复。在另一个实验中，连续两天注射可卡因引发剂，重新激活可卡因记忆。在这两天，人工脑脊液（aCSF）或FN-439在可卡因引发的恢复期之前30分钟或之后1分钟给药。输注FN-439部分损害了可卡因相关背景的检索时，给予可卡因前30分钟。然而，在两组中，与对照组相比，FN-439抑制了可卡因引发的恢复的连续第三次测试，当没有给予FN-439时。对照实验表明，在饲养笼中给予两次FN-439 +可卡因注射，或在CPP室中给予两次FN-439 +盐水预充注射，不会破坏随后的可卡因预充恢复。这些结果首次表明：（1）MMP在可卡因诱导的CPP的获得和再巩固中起关键作用，（2）大鼠在消退后和恢复期间在可卡因的影响下表现出明显的MMP抑制剂对再巩固的破坏。
Persistent drug seeking/taking behavior involves the consolidation of memory. With each drug use, the memory may be reactivated and reconsolidated to maintain the original memory. During reactivation, the memory may become labile and susceptible to disruption; thus, molecules involved in plasticity should influence acquisition and/or reconsolidation. Recently, matrix metalloproteinases (MMPs) have been shown to influence neuronal plasticity, presumably by their regulation of extracellular matrix (ECM) molecules involved in synaptic reorganization during learning. We hypothesized that inhibition of MMP activity would impair the acquisition and/or reconsolidation of cocaine-conditioned place preference (CPP) in rats. Intracerebral ventricular (i.c.v.) microinjection of a broad spectrum MMP inhibitor, FN-439, prior to cocaine training suppressed acquisition of CPP and attenuated cocaine-primed reinstatement in extinguished animals. In a separate experiment, the cocaine memory was reactivated on two consecutive days with a cocaine priming injection. On these two days, artificial cerebral spinal fluid (aCSF) or FN-439 was administered either 30 min prior to or 1 min after cocaine-primed reinstatement sessions. Infusion of FN-439 partially impaired retrieval of the cocaine-associated context when given 30 min prior to cocaine. In both groups, however, FN-439 suppressed reinstatement compared with controls on the third consecutive test for cocaine-primed reinstatement, when no FN-439 was given. Control experiments demonstrated that two injections of FN-439 + cocaine given in the home cage, or of FN-439 + saline priming injections in the CPP chambers did not disrupt subsequent cocaine-primed reinstatement. These results show for the first time that (1) MMPs play a critical role in acquisition and reconsolidation of cocaine-induced CPP, and (2) rats demonstrate apparent disruption of reconsolidation by an MMP inhibitor after extinction and while they are under the influence of cocaine during reinstatement.