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MEMORY PROCESSES GOVERNING PSYCHOSTIMULANT SENSITIZATION

控制精神兴奋剂致敏的记忆过程

基本信息

批准号：
6831484
负责人：
STEPHAN G ANAGNOSTARAS
金额：
$ 4.53万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-10 至 2005-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6831484
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

项目摘要

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（由申请人提供）：行为过敏是由于重复间歇性使用兴奋剂药物引起的，并且可能导致成瘾。先前的研究调查了情境刺激与精神兴奋剂的关联配对对啮齿类动物精神运动敏化表达的影响，结果表明，在某些情况下，敏化可能是特定于情境的。基于这些和其他发现，我们提出三种记忆机制调节刺激物敏化的情境特异性：（1）重复给药会诱导神经基质的敏化，从而介导对药物的无条件反应（UR），这是一种非联想学习的形式。 (2) 抑制过程可以在不需要药物的情况下阻断神经敏化的表达，这是一个涉及抑制场合设置的过程。 (3) 兴奋性条件反应 (CR) 可以在预期使用药物的情况下放大敏化反应，并在没有药物的情况下产生 CR，这可能会导致渴望。药物相关环境通过情境设置调节神经敏化表达的能力可能与药物相关环境产生条件反应的能力相结合，共同提供强大的联想控制，不仅对行为敏化，而且对成瘾者的渴望和复发。在当前的提案中，我们将研究不同的神经记忆系统是否选择性地介导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，以研究刺激物敏化背后的记忆过程，开发一种产生强大敏化、快速获取（以便可以检查不同记忆阶段）的程序，并测量敏化、情境特异性和条件反应。建立这一范式后，我们将尝试通过检查与记忆相关的大脑结构（包括海马体和杏仁核）损伤的影响来确定这些过程的关键神经基质。最后，利用这种新颖的小鼠范例，我们将研究这些过程的分子神经生物学，检查具有已知会破坏记忆的目标基因突变的小鼠。这种使用系统和分子方法的方法应该阐明已知对学习和记忆重要的结构和基因是否对于刺激物致敏的表达也同样重要。