Feltenstein Matthew W, See Ronald E
Department of Neurosciences, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.
Neurobiol Learn Mem. 2007 Nov;88(4):435-44. doi: 10.1016/j.nlm.2007.05.006. Epub 2007 Jul 5.
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 1-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 microl/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.
我们实验室之前的研究表明，基底外侧杏仁核（BLA）复合体参与线索-可卡因关联的获得与巩固，以及消退学习，消退学习可能调节条件刺激（CS）对觅药行为的长期控制。鉴于NMDA谷氨酸受体激活在其他形式的基于杏仁核的学习中已确立的作用，我们预测BLA介导的药物-线索联想学习将依赖于NMDA受体。为了验证这一假设，雄性Sprague-Dawley大鼠在没有明确CS配对的情况下静脉注射可卡因（0.6mg/kg/次输注）（2小时 sessions，共5天），随后进行一次1小时的经典条件反射（CC）session，在此期间，它们接受与光+音刺激复合体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session（2小时 sessions，共5天）和消退训练session（无可卡因或CS呈现，2小时 sessions，共7天）后，评估CS在三个测试日恢复可卡因觅求的能力。大鼠在CC session（获得）之前、CC session之后（巩固）或恢复测试之后（条件线索消退学习的巩固）立即接受双侧BLA内注射（0.5微升/半球）媒介物或选择性NMDA受体拮抗剂2-氨基-5-磷酸戊酸（AP-5）。在CC之前或之后给予AP-5会减弱随后CS诱导的恢复，而在前两次恢复测试后立即给予AP-5会损害可卡因觅求行为的消退。这些结果表明，BLA内NMDA受体介导的机制在将药物-CS关联巩固为长期记忆中起关键作用，而长期记忆又会在复发期间驱动可卡因觅求。
