NEURAL AND MOLECULAR MECHANISMS IN STRIATAL LEARNING

描述：(申请者摘要)滥用药物已成为一种主要的社会问题 以及美国、南美和欧洲的医疗问题。 目前，据估计有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 药物涉及的不同神经系统和分子机制 上瘾。伏隔核和纹状体的其他区域 此前曾被牵连参与调节运动激活和 增强可卡因等精神刺激性药物的作用。此外, 研究表明，纹状体的这些亚区也 调节不同学习记忆功能和兴奋性氨基酸 皮层和边缘投射的酸性(EAA)神经传递 纹状体区域调节这些功能。代谢性谷氨酸 受体(MGluRs)是纹状体中发现的一种EAA受体，它似乎 对突触可塑性和学习有调节作用。海流 该提案旨在进一步研究EAA的神经传递和 纹状体不同亚区的蛋白激酶C， 在大鼠身上使用行为-药理学-分子方法。至 为了实现这一目标，直接脑内微量输注实验药物将 与衡量空间的行为范式结合使用 学习、静脉注射可卡因自我给药反应与 恢复寻找可卡因的行为。有两个主要目标 拟议的实验：1)表征mGluRs在 纹状体区对正常和非正常学习的控制作用 可卡因引起的行为反应。2)研究蛋白质的作用 不同纹状体中不同纹状体区域的激酶C活性 学习功能。拟议研究计划的结果可能会提供新的 了解：1)EAA受体的功能作用，特别是 纹状体中的mGluRs，2)分子机制 通过参与不同形式纹状体调制的PKC 学习，以及3)EAA受体和PKC活性在脑内的作用 伏隔核在可卡因强化和可卡因诱导中的作用 寻求行为。

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.