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）：行为敏化是由于反复间歇性使用刺激药物而导致的，并可能导致成瘾。先前研究的研究调查了上下文刺激与精神刺激施用对啮齿动物中精神运动敏化表达的影响的影响，表明在某些情况下，敏化可能是特定于上下文的。基于这些发现和其他发现，我们提出，三种记忆机制调节了刺激性敏化的上下文特异性：（1）重复给药诱导神经底物的敏化，从而介导对药物的无条件反应（UR），这是一种非相关学习的一种形式。（2）抑制过程可以阻止在没有预期的药物的情况下，这是涉及抑制场合设定的过程。（3）在预期药物的情况下，兴奋性条件反应（CR）可以扩增敏化反应，并产生CR，在没有药物的情况下可能有助于渴望。与药物相关的环境通过设定时调节神经敏化表达的能力可能与药物相关背景产生条件反应的能力相结合，共同对不仅对行为敏化，而且在成瘾者中，渴望过分渴望和复发。在当前的建议中，我们将研究不同的神经记忆系统是否有选择地介导与行为敏化有关的记忆过程。首先，我们将使用小鼠优化行为范式，用于研究刺激剂敏化的内存过程，开发一种过程，该过程产生强大的敏感性，快速获取（以便可以检查不同的记忆阶段），并测量灵敏度，上下文特异性和条件响应。在建立此范式之后，我们将尝试通过检查与记忆相关的大脑结构（包括海马和杏仁核）病变的影响来识别这些过程的关键神经底物。最后，使用这种新颖的小鼠范式，我们将研究这些过程的分子神经生物学，以已知破坏记忆的靶向基因突变检查小鼠。使用系统和分子方法，这种方法应阐明对学习和记忆很重要的结构和基因是否对刺激性敏化的表达同样至关重要。