Drug Context-Induced Instrumental Cocaine Seeking: Influence of Memory Reconsolid

药物环境诱发的工具性可卡因寻求：记忆重建的影响

• 批准号: 8794505
• 负责人: Rita A Fuchs Lokensgard
• 金额: $ 30.78万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8794505
• 关键词: Drug; Context; Induced; Instrumental; Cocaine

DESCRIPTION (provided by applicant): Successful treatment of cocaine dependence must involve the prevention of environmentally-induced cocaine relapse. Drug-context-induced cocaine relapse relies on the utilization of long-term memories of context- response-cocaine associations. These associative memories can become labile upon retrieval, and must undergo protein synthesis-dependent re-stabilization (i.e., reconsolidation) in order to be maintained in long- term memory. Abnormally enhanced memory reconsolidation may contribute to intrusive thoughts about cocaine and strong cue reactivity, which are the hallmarks of drug addiction. Hence, manipulations that disrupt cocaine memory reconsolidation or inhibit pathological cocaine memories are of tremendous interest from an addiction treatment perspective. Understanding the putative relationship between pathological cocaine memory reconsolidation and drug relapse is a complex problem that requires a two-part approach: (1) identification of the neurobiological substrates of memory reconsolidation that promote drug-context-induced drug seeking and (2) discovery of pathology within these substrates. Focusing on the first objective, the overarching goal of this project is to elucidate essential, and previously uncharacterized, functional neuroanatomical and cellular mechanisms of memory reconsolidation that facilitate drug-context-induced instrumental cocaine seeking. The project will rely upon our previous work, which has demonstrated that protein synthesis in the basolateral amygdala (BLA) and the functional integrity of the dorsal hippocampus (DH) are necessary for cocaine memory reconsolidation and subsequent drug-context-induced cocaine seeking in rats. However, it is unclear whether there is obligatory interaction between these brain regions. Thus, Aim 1 will be to begin to map the putative cocaine memory reconsolidation circuitry. Experiments will test the hypothesis that sequential information processing by the DH and BLA is required for cocaine memory reconsolidation that facilitates subsequent context-induced cocaine seeking. Additional experiments will evaluate whether the nucleus accumbens core and shell, two efferents of the above brain regions, are a part of this circuitry. Based on our previous work, Aim 2 will center on putative cellular mechanisms of cocaine memory reconsolidation in the BLA. It has been postulated that cocaine-induced neuroplasticity, notably enhanced cAMP- and Ca2+ dependent cellular signaling, may trigger pathological memory reconsolidation. To examine two basic assumptions of this idea, experiments will test the hypothesis that (A) the activity of these pathways in the BLA is necessary for cocaine memory reconsolidation and that (B) mimicking the increase in the activity of these signaling pathways putatively produced by chronic cocaine administration is sufficient to potentiate cocaine memory reconsolidation and context-induced cocaine seeking. In sum, this project will explore the neurobiology of cocaine memory reconsolidation to provide a rationale for future research into pathological cocaine memory reconsolidation and for the development of novel pharmacotherapies for drug addiction.

描述(申请人提供)：成功的可卡因依赖治疗必须包括预防环境引起的可卡因复发。药物情境诱导的可卡因复发依赖于对情境-反应-可卡因联系的长期记忆的利用。这些联想记忆在提取时可能变得不稳定，必须经历依赖蛋白质合成的重新稳定(即重新巩固)，才能维持在长期记忆中。异常增强的记忆再巩固可能会导致对可卡因的侵入性想法和强烈的线索反应，这是吸毒成瘾的特征。因此，从成瘾治疗的角度来看，扰乱可卡因记忆再巩固或抑制病理性可卡因记忆的操作是非常有意义的。了解病理性可卡因记忆再巩固和药物复发之间的可能关系是一个复杂的问题，需要两个部分的方法：(1)识别促进药物情境诱导的药物寻求的记忆再巩固的神经生物学底物；(2)在这些底物中发现病理学。着眼于第一个目标，本项目的首要目标是阐明记忆重新巩固的基本和以前未被表征的功能性神经解剖学和细胞机制，这些机制促进了药物背景诱导的器质性可卡因寻找。该项目将依赖于我们之前的工作，该工作已经证明，杏仁基底外侧核(BLA)的蛋白质合成和背侧海马区(DH)的功能完整性对于可卡因记忆的重新巩固和随后的药物诱导的可卡因寻找是必要的。然而，目前还不清楚这些大脑区域之间是否存在强制性的相互作用。因此，目标1将是开始绘制推测的可卡因记忆重新巩固电路。实验将检验这一假设，即DH和BLA的顺序信息处理是可卡因记忆重新巩固所必需的，这有助于随后的上下文诱导的可卡因寻找。其他实验将评估伏隔核的核心和外壳--上述脑区的两个传出神经--是否是这一回路的一部分。在我们以前工作的基础上，目标2将集中在BLA中可卡因记忆重新巩固的假定细胞机制上。据推测，可卡因诱导的神经可塑性，尤其是cAMP和钙依赖的细胞信号显著增强，可能触发病理性记忆再巩固。为了检验这一想法的两个基本假设，实验将检验这样的假设：(A)在BLA中这些通路的活动是可卡因记忆再巩固所必需的，以及(B)模拟这些信号通路的活性增加可能是由长期服用可卡因所产生的，足以加强可卡因记忆的再巩固和上下文诱导的可卡因寻找。综上所述，本项目将探索可卡因记忆再巩固的神经生物学，为未来病理性可卡因记忆再巩固的研究和药物成瘾新药物疗法的开发提供理论基础。