Behavior/Drug Interactions in Striatal gene Regulation

纹状体基因调节中的行为/药物相互作用

• 批准号: 6637748
• 负责人: Heinz Steiner
• 金额: $ 15.6万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637748
• 关键词: behavior modification; behavioral /social science research tag; behavioral genetics; cocaine; corpus striatum; dopamine receptor; drug addiction; dynorphins; fos protein; gene expression; genetic markers; genetic regulation; glutamate receptor; histochemistry /cytochemistry; in situ hybridization; laboratory rat; neurons; neuropeptides; neuropsychology; protooncogene; transcription factor

DESCRIPTION: (provided by applicant) Exposure to psychostimulants such as cocaine and amphetamine causes behavioral changes including addiction and dependence. Addiction is defined by compulsive drug taking and may involve abnormal motor learning/habit formation, a function that has been ascribed to dorsal parts of the striatum. Motor learning likely involves modification of synaptic connections and altered gene regulation. Many studies have shown that psychostimulants produce changes in the expression of various genes, including genes that encode transcription factors, structural proteins and signaling molecules. Moreover, such gene regulation preferentially occurs in dorsal striatal sectors that are part of "motor" loops that interconnect the cortex and the basal ganglia. Neuronal changes related to motor learning/habit formation would be expected to be triggered during (or in close association with) motor performance and be related to such performance. The experiments of the present proposal will investigate whether the behavior performed during the influence of cocaine can modify neuronal changes produced by cocaine. Thus, we propose to test the hypothesis that different behaviors during cocaine action will be associated with different changes in gene expression in striatal neurons. Differential "behavioral treatment" will consist of repeated exposure to a running wheel vs. a small open field immediately after the cocaine injection. In situ hybridization histochemistry will be used to compare changes in gene expression in various striatal sectors between such differentially treated rats. Initially, a short-term molecular marker (c-fos induction by a cocaine challenge) and longer-term markers (neuropeptides such as dynorphin) will be assessed. As a first step to determine behavioral effects, open-field behavior induced by a cocaine or vehicle challenge will be examined subsequent to the repeated treatments. These studies should provide new insights into how the behavior executed during the drug action can influence drug-induced neuroplasticity in the striaturn.

描述：（申请人提供） 接触可卡因和安非他明等精神兴奋剂会导致行为 变化包括成瘾和依赖。成瘾的定义是强迫性 可能涉及异常的运动学习/习惯形成，一种功能 被认为是纹状体的背侧部分。可能是运动学习 涉及突触连接的修饰和基因调控的改变。许多 研究表明，精神兴奋剂会改变 各种基因，包括编码转录因子的基因，结构 蛋白质和信号分子。此外，这种基因调控优先 发生在背侧纹状体部分，是“运动”回路的一部分， 连接皮层和基底神经节 与运动学习/习惯形成相关的神经元变化预计将 在运动表现期间（或与运动表现密切相关）被触发， 与这样的业绩有关。本提案的实验将 调查可卡因影响期间的行为是否可以 改变可卡因引起的神经元变化因此，我们建议测试 假设可卡因作用期间的不同行为将与 纹状体神经元基因表达的不同变化。微分 “行为治疗”将包括反复暴露于运行的车轮与 在注射可卡因后立即留下一小块空地原位 杂交组织化学将用于比较基因表达的变化 在这些不同处理的大鼠之间的各种纹状体区。 最初，短期分子标记（可卡因诱导的c-fos） 挑战）和长期标志物（神经肽，如强啡肽）将被 评估。作为确定行为效应的第一步， 由可卡因或溶媒激发诱导的试验将在 反复治疗。这些研究应该提供新的见解， 在药物作用期间执行的行为可以影响药物诱导的 纹状体的神经可塑性