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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）：行为敏感化是由重复间歇使用兴奋剂药物引起的，可能导致成瘾。先前的研究调查关联配对的上下文刺激与精神兴奋剂管理的啮齿动物的心理敏化的表达的影响表明，在某些情况下，敏化可以是特定的上下文。基于这些和其他研究结果，我们提出了三种记忆机制调节刺激敏化的情境特异性：（1）重复给药诱导神经基质敏化，介导对药物的无条件反应（UR），这是一种非联想学习形式。(2)抑制性过程可以在不期望药物的情况下阻断神经敏化的表达，这是一个涉及抑制性兴奋设定的过程。(3)兴奋性条件反应（CR）可以在预期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，这可能有助于渴望。与药物相关的环境通过成瘾设定调节神经敏感化表达的能力可能与与药物相关的环境产生条件反应的能力联合收割机结合，一起提供不仅对行为敏感化，而且对成瘾者的渴望和复发的强大关联控制。在目前的建议中，我们将调查，如果不同的神经记忆系统选择性地介导的记忆过程中涉及的行为敏化。首先，我们将使用小鼠来优化行为范式，以研究刺激物致敏背后的记忆过程，开发一种产生强大的致敏，快速获取（以便可以检查不同的记忆阶段）的程序，并测量致敏，上下文特异性和条件反应。建立这种范式后，我们将试图通过研究与记忆相关的脑结构（包括海马和杏仁核）病变的影响来确定这些过程的关键神经基质。最后，使用这种新的小鼠范例，我们将研究这些过程的分子神经生物学，检查具有已知会破坏记忆的靶向基因突变的小鼠。这种方法，使用系统和分子的方法，应该阐明是否结构和基因已知是重要的学习和记忆是同样重要的表达刺激敏化。