应激在非条件性刺激诱导的药物奖赏记忆再巩固中的作用及神经机制

Drug addiction is a serious public health and social problem. The key point in treatment of drug addiction is how to control relapse after withdrawal.The persistence of drug reward memory induced by repeatedly exposure to abused drugs caused high rate of relapse to drug seeking. Recently, it has been reported that disruption of the reconsolidation of drug reward memory decreased the drug craving and seeking in the addicts, which inhibited the relapse to drug reconsumption. Either exposure to conditioned stimulus (CS) or unconditioned stimulus (UCS) induced the memory reconsolidation. Previous studies have found that stress has important regulatory role in consolidation, retrieval and reconsolidation of memory and that stress impaired the CS-induced reconsolidation. In the current project, behavioral, molecular pharmacologic methods will be integrated with conditioned place preference and self-administration rats model to investigate the role of stress in reconsolidation of pathological reward memory induced by abused drugs. Furthermore, the underlying mechanisms regarding the role of glucocorticoid receptors signaling pathway in the basolateral amygdala (BLA) in the UCS-induced reconsolidation of drug reward memory will be investigated. Development of the current projection will be helpful for uncovering mechanisms of drug addiction and for promoting the treatment of addiction and prevention of relapse.

药物成瘾是严峻的公共卫生以及社会问题。复吸是药物成瘾治疗的关键问题。成瘾性药物诱导的药物奖赏记忆的持续存在是导致成瘾者戒断后高复吸率的根本原因。近年来，研究表明破坏药物奖赏记忆的再巩固过程能够降低成瘾者的心理渴求，从而抑制复吸。条件性（CS）或者非条件性刺激（UCS）暴露都可以诱导记忆发生记忆的再巩固过程。应激在记忆的巩固、唤起和再巩固，均发挥重要的调节作用。应激可以破坏条件性刺激诱导的药物奖赏记忆的再巩固过程。我们的前期研究发现非条件性刺激的暴露可以诱导药物奖赏记忆发生再巩固过程。本项目拟运用行为学、分子药理学方法，在条件性位置偏爱和自身给药大鼠模型中，研究应激对非条件性诱导的药物奖赏记忆再巩固影响，并探讨基底外侧杏仁核脑区糖皮质激素信号通路在调控非条件性刺激诱导的药物奖赏记忆再巩固中的作用。本项目将在丰富对药物成瘾机制认识的同时，也为治疗药物成瘾以及预防复吸拓宽思路。

药物成瘾不但是严峻的公共卫生同时也是非常严重的社会问题。反复的成瘾性药物暴露导致的药物奖赏记忆的持续存在是成瘾者戒断后高复吸率的根本原因。复吸是药物成瘾治疗的关键问题。大量研究表明药物成瘾是一种异常的病理性情感记忆，破坏药物奖赏记忆的再巩固过程能够降低成瘾者的心理渴求，从而抑制复吸。因此，以干预药物奖赏记忆的再巩固过程为靶向的预防复吸的重要研究方向。应激在记忆的巩固、唤起和再巩固，均发挥重要的调节作用。在本课题中，我们运用行为学、分子药理学方法，在条件性位置偏爱 (Conditioned place preference, CPP )和自身给药 (Self-administration, SA )大鼠模型中，研究应激对非条件性刺激 (Unconditioned Stimulus, UCS )诱导的药物奖赏记忆巩固影响，并探讨基底外侧杏仁核脑区（Basolateral amygdala, BLA）糖皮质激素信号通路在调控非条件性刺激诱导的药物奖赏记忆再巩固中的作用。本项目将在丰富对药物成瘾机制认识的同时，也为治疗药物成瘾以及预防复吸拓宽思路。运用行为学、分子药理学方法，在条件性位置偏爱和自身给药大鼠模型中，研究应激对非条件性诱导的药物奖赏记忆巩固影响，并探讨基底外侧杏仁核脑区糖皮质激素信号通路在调控非条件性刺激诱导的药物奖赏记忆再巩固中的作用。我们发现：1）在UCS诱导的再巩固时间窗内应激可以破坏奖赏性药物诱导的成瘾记忆；2）应激破坏非条件性刺激诱导的药物奖赏记忆再巩固抑制大鼠觅药行为复燃；3）应激破坏非条件性刺激诱导的药物奖赏记忆再巩固抑制大鼠觅药行为的自发恢复；4) BLA脑区中的糖皮质激素信号通路参与调控非条件性刺激诱导的药物奖赏记忆的再巩固过程； 5）应激破坏非条件性刺激诱导的药物奖赏记忆再巩固抑制多个伴药线索诱导的大鼠觅药行为。综上，应激可以通过激活BLA脑区的糖皮质激素信号通路破坏UCS诱导的药物奖赏性记忆再巩固，从而降低药物渴求和防止复吸。