NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse
NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse
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DOI：
10.1016/j.nlm.2007.05.006
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发表时间：
2007-11-01
影响因子：
2.7
通讯作者：
See, Ronald E.
中科院分区：
文献类型：
--
作者：
Feltenstein, Matthew W.;See, Ronald E.
我们实验室以前的研究表明，基底外侧杏仁核（BLA）复合体参与了线索-可卡因关联的获得和巩固，以及消退学习，这可能会调节条件刺激（CS）对药物寻求行为的长期控制。鉴于NMDA谷氨酸受体激活在其他形式的杏仁核为基础的学习中的既定作用，我们预测，BLA介导的药物线索联想学习将是NMDA受体依赖性的。为了验证这一假设，雄性Sprague-Dawley大鼠在没有明确CS配对的情况下自我静脉注射可卡因（0.6 mg/kg/输注）（2小时会议，5天），然后进行单次I-h经典条件反射（CC）会议，在此期间，它们接受了与光+音调刺激复合物离散配对的可卡因被动输注。在没有CS的情况下进行额外的可卡因自我给药会话（2小时会话，5天）和消退训练会话（无可卡因或CS呈现，2小时会话，7天）后，评估CS在三个测试日恢复可卡因寻求的能力。大鼠接受双侧BLA内输注（0.5 μ l/半球）的车辆或选择性NMDA受体拮抗剂，2-氨基-5-膦酰基戊酸酯（AP-5），之前立即CC会议（收购），后立即CC会议（巩固），或后立即恢复测试（巩固条件提示消退学习）。在CC之前或之后给予AP-5减弱了随后的CS诱导的恢复，而在前两次恢复测试之后立即给予AP-5则损害了可卡因寻求行为的消退。这些结果表明，BLA内的NMDA受体介导的机制在将药物-CS关联巩固为长期记忆方面发挥着至关重要的作用，而长期记忆反过来又会在复发期间驱动可卡因寻求。(C)2007爱思唯尔公司All rights reserved.
Previous research from our laboratory has implicated the basolateral amygdala (BLA) complex in the acquisition and consolidation of cue-cocaine associations, as well as extinction learning, which may regulate the long-lasting control of conditioned stimuli (CS) over drug-seeking behavior. Given the well established role of NMDA glutamate receptor activation in other forms of amygdalar-based learning, we predicted that BLA-mediated drug-cue associative learning would be NMDA receptor dependent. To test this hypothesis, male Sprague-Dawley rats self-administered i.v. cocaine (0.6 mg/kg/infusion) in the absence of explicit CS pairings (2-h sessions, 5 days), followed by a single I-h classical conditioning (CC) session, during which they received passive infusions of cocaine discretely paired with a light + tone stimulus complex. Following additional cocaine self-administration sessions in the absence of the CS (2-h sessions, 5 days) and extinction training sessions (no cocaine or CS presentation, 2-h sessions, 7 days), the ability of the CS to reinstate cocaine-seeking on three test days was assessed. Rats received bilateral intra-BLA infusions (0.5 mu l/hemisphere) of vehicle or the selective NMDA receptor antagonist, 2-amino-5-phosphonovalerate (AP-5), immediately prior to the CC session (acquisition), immediately following the CC session (consolidation), or immediately following reinstatement testing (consolidation of conditioned-cued extinction learning). AP-5 administered before or after CC attenuated subsequent CS-induced reinstatement, whereas AP-5 administered immediately following the first two reinstatement tests impaired the extinction of cocaine-seeking behavior. These results suggest that NMDA receptor-mediated mechanisms within the BLA play a crucial role in the consolidation of drug-CS associations into long-term memories that, in turn, drive cocaine-seeking during relapse. (C) 2007 Elsevier Inc. All rights reserved.