NEURAL AND MOLECULAR MECHANISMS IN STRIATAL LEARNING

纹状体学习中的神经和分子机制

• 批准号: 6350519
• 负责人: CARMEN Sara MALDONADO-VLAAR
• 金额: $ 8.74万
• 依托单位: UNIVERSITY OF PUERTO RICO RIO PIEDRAS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-20 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350519
• 关键词: antisense nucleic acid; association learning; behavior test; behavioral /social science research tag; cocaine; corpus striatum; drug abuse; drug addiction; excitatory aminoacid; glutamate receptor; laboratory rat; learning; memory; microinjections; motivation; nucleus accumbens; protein kinase C; reinforcer; self medication; substance abuse related behavior

DESCRIPTION: (Applicant's Abstract) Drug abuse has become a major social and medical problem in the United States, South America and Europe. Presently, it is estimated that there are over 2 million regular drug users in the USA. One of the main goals of neurobiological research is to study the different neural systems and molecular mechanisms involved in drug addiction. The nucleus accumbens and other areas of the corpus striatum have previously been implicated in mediating the motor activation and reinforcing effects of psychostimulant drugs such as cocaine. In addition, studies have demonstrated that these subregions of the striatum also regulate different learning and memory functions and that excitatory amino acid (EAA) neurotransmission from cortical and limbic projections to these striatal regions modulate these functions. The metabotropic glutamate receptor (mGluRs) is a type of EAA receptor found in the striatum that seems to have modulatory effects in synaptic plasticity and learning. The current proposal seeks to further investigate EAA neurotransmission and the role of protein kinase C within the different subregions of the corpus striatum, using a behavioral-pharmacological-molecular approach in the rat. To accomplish this goal, direct brain microinfusions of experimental drugs will be utilized in conjunction with behavioral paradigms that measure: spatial learning, intravenous cocaine self-administration responding and the reinstatement of cocaine seeking behavior. There are two major goals of the proposed experiments: 1) To characterize the role that mGluRs within the corpus striatum play in controlling learning related to both normal and cocaine-induced behavioral response. 2) To examine the role of Protein Kinase C activation within different striatal regions in distinct striatal learning functions. Results from the proposed research plan may provide new knowledge on: 1) the functional roles of EAA-receptors and, specifically the mGluRs, in the corpus striatum, 2) the molecular mechanisms controlled by PKC that are involved in the modulation of different forms of striatal learning, and 3) the role of EAA receptors and PKC activity within the nucleus accumbens in mediating cocaine reinforcement and eliciting cocaine seeking behavior.

药物滥用已成为一个主要的社会问题， 和医疗问题在美国，南美和欧洲。 目前，估计有200多万经常吸毒者， 在美国。 神经生物学研究的主要目标之一是研究 不同的神经系统和分子机制参与药物 成瘾 纹状体的脑桥核和其他区域 先前参与介导运动激活， 可卡因等精神兴奋剂的强化作用。 此外，本发明还提供了一种方法， 研究表明，纹状体的这些亚区也 调节不同的学习和记忆功能， 酸（EAA）神经传递从皮质和边缘投射到这些 纹状体区域调节这些功能。 代谢型谷氨酸 受体（mGluRs）是一种在纹状体中发现的EAA受体， 对突触可塑性和学习有调节作用。 当前 建议旨在进一步研究EAA神经传递和作用， 纹状体不同亚区内的蛋白激酶C， 使用行为药理学分子方法。 到 为了实现这一目标，直接向大脑微量输注实验药物将 结合行为范式来衡量：空间 学习，静脉注射可卡因自我管理响应和 恢复可卡因寻求行为。 有两个主要目标， 提出的实验：1）为了表征mGluRs在细胞内的作用， 纹状体在控制学习中发挥作用， 可卡因引起的行为反应 2)研究蛋白质的作用 在不同的纹状体中不同纹状体区域内的激酶C激活 学习功能。 从拟议的研究计划的结果可能提供新的 知识：1）EAA受体的功能作用，特别是 纹状体中的mGluRs，2）分子机制控制 PKC参与不同形式的纹状体神经元的调节， 学习，和3）EAA受体和PKC活性的作用， 延髓核介导可卡因强化和诱发可卡因 寻求行为。