MEMORY PROCESSES GOVERNING PSYCHOSTIMULANT SENSITIZATION

控制精神兴奋剂致敏的记忆过程

• 批准号: 6672161
• 负责人: STEPHAN G ANAGNOSTARAS
• 金额: $ 3.07万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-10 至 2003-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6672161
• 关键词: amygdala; behavioral /social science research tag; behavioral genetics; behavioral habituation /sensitization; cocaine; drug abuse; drug hypersensitivity; experimental brain lesion; gene expression; gene mutation; hippocampus; laboratory mouse; memory; neural information processing; stimulus /response; substance abuse related behavior

DESCRIPTION (provided by applicant): Behavioral sensitization results from repeated intermittent use of stimulant drugs, and may contribute to addiction. Prior studies investigating the influence of associative pairing of contextual stimuli with psychostimulant administration on the expression of psychomotor sensitization in rodents have shown that under certain circumstances, sensitization can be context-specific. Based on these and other findings, we proposed that three memory mechanisms regulate the context-specificity of stimulant sensitization: (1) Repeated drug administration induces sensitization of the neural substrate that mediates the unconditional response (UR) to the drug, a form of non-associative learning. (2) An inhibitory process can block the expression of neural sensitization in contexts where the drug is not expected, a process involving inhibitory occasion-setting. (3) An excitatory conditioned response (CR) can amplify the sensitized response in a context where the drug is expected, and produces a CR, which may contribute to craving, in the absence of the drug. The ability of drug-associated contexts to modulate the expression of neural sensitization via occasion-setting may combine with the ability of a drug-associated context to produce conditioned responses, together providing powerful associative control over not only behavioral sensitization, but in addicts, over craving and relapse. In the current proposal, we will investigate if distinct neural memory systems selectively mediate memory processes involved in behavioral sensitization. First, we will use mice to optimize the behavioral paradigm for studying memory processes underlying stimulant sensitization, developing a procedure which produces robust sensitization, rapid acquisition (so that distinct memory phases may be examined), and measuring sensitization, context-specificity, and conditioned responses. Following establishment of this paradigm, we will attempt to identify critical neural substrates of these processes by examining the impact of lesions of memory-related brain structures, including the hippocampus and amygdala. Finally, using this novel mouse paradigm, we will investigate the molecular neurobiology of these processes, examining mice with targeted genetic mutations known to disrupt memory. This approach, using systems and molecular methods, should elucidate whether structures and genes known to be important for learning and memory are similarly crucial for the expression of stimulant sensitization.

描述(申请人提供)：行为敏感化是反复间歇使用兴奋剂引起的，可能会导致上瘾。先前的研究发现，在啮齿类动物中，语境刺激与心理刺激剂的联合作用对精神运动敏化表达的影响已经表明，在某些情况下，敏化可以是特定于语境的。基于这些和其他发现，我们提出了三种记忆机制来调节刺激剂敏化的背景-特异性：(1)重复给药诱导神经基质的敏化，该神经基质介导对药物的无条件反应(UR)，这是一种非联想学习形式。(2)抑制过程可以在药物不被期望的情况下阻止神经敏化的表达，这是一个涉及抑制时机设置的过程。(3)兴奋性条件性反应(CR)可以在药物预期的情况下放大致敏反应，并在没有药物的情况下产生CR，这可能有助于渴望。药物相关环境通过情景设置调节神经敏化表达的能力可以与药物相关环境产生条件性反应的能力结合在一起，不仅对行为敏感化，而且对成瘾者的渴望和复发提供强大的联合控制。在目前的方案中，我们将研究不同的神经记忆系统是否选择性地调节涉及行为敏化的记忆过程。首先，我们将使用小鼠来优化行为范式，以研究刺激敏化背后的记忆过程，开发一种程序，产生强大的敏化、快速获取(以便可以检查不同的记忆阶段)，并测量敏化、上下文专一性和条件性反应。随着这一范式的建立，我们将试图通过检查与记忆相关的大脑结构(包括海马体和杏仁核)的损伤的影响来确定这些过程的关键神经底物。最后，使用这一新的小鼠范例，我们将研究这些过程的分子神经生物学，检查已知具有破坏记忆的靶向基因突变的小鼠。这种方法，使用系统和分子方法，应该阐明已知的对学习和记忆重要的结构和基因是否对刺激剂敏化的表达同样至关重要。