Cholecystokinin and anxiety

胆囊收缩素和焦虑

• 批准号: 8065944
• 负责人: Saobo Lei
• 金额: $ 30.07万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065944
• 关键词: 1,2-diacylglycerol; Adverse effects; Affect; American; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Binding; Brain; Brain region; Cells; Cholecystokinin; Cholecystokinin B Receptor; Cholecystokinin Receptor; Conflict (Psychology); Coupled; Data; Dependence; Development; Diglycerides; Disease; Emotions; G-Protein-Coupled Receptors; Gastrointestinal tract structure; Generations; Glutamate Receptor; Glutamates; Health; Hippocampus (Brain); Individual; Inositol; Knockout Mice; Limbic System; Measurement; Mediating; Membrane; Mental disorders; Modeling; Molecular; Moods; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Neurons; Neuropeptides; Panic Attack; Pathogenesis; Pathway interactions; Perforant Pathway; Pharmaceutical Preparations; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipase C; Potassium Channel; Principal Investigator; Probability; Process; Protein Kinase C; Research; Role; Signal Transduction; Signaling Molecule; Structure; Synapses; System; Testing; Time; Toxin; citrate carrier; density; dentate gyrus; effective therapy; granule cell; hippocampal pyramidal neuron; innovation; interest; meetings; novel; novel strategies; novel therapeutics; presynaptic; prevent; programs; receptor; receptor function; response; success; transmission process

DESCRIPTION (provided by applicant): Anxiety is one of the most prevalent psychiatric disorders in the U.S.A., currently affecting ~20 million individuals. The currently available anxiolytics, while somewhat effective, have side effects and target a limited number of mechanisms. Exploring novel mechanisms or strategies to treat anxiety is still an arduous task. Whereas tremendous studies indicate an important role for cholecystokinin (CCK) system in the pathogenesis of anxiety, the underlying cellular and molecular mechanisms remain unsolved. Because elevation in glutamatergic functions underlies the generation of anxiety, we have examined the effects of CCK on glutamatergic transmission in the hippocampus, a structure closely involved in the processing of context-related information and the expression of anxiety responses to environmental signals. We have substantial preliminary data demonstrating that CCK increased glutamate release at multiple synapses of the hippocampus via inhibition of the delayed rectifier K+ channels (IK). We have also shown that CCK increased NMDA type of glutamate receptor-mediated currents in isolated hippocampal neurons. The effects of CCK on glutamate release and NMDA receptor function were mediated by CCK-2 receptors and required the functions of phospholipase C (PLC) and protein kinase C (PKC). Using two animal anxiety models (Elevated plus maze and Vogel Conflict test), we demonstrated that CCK-induced increase in anxiety was mediated via ionotropic glutamate receptors. The objective of this project is to determine the involved detailed cellular and molecular mechanisms by testing the hypothesis that CCK-induced increase in glutamatergic function is responsible for its anxiogenic effects. Specific Aim 1 will identify the detailed ionic and signaling mechanisms underlying CCK-mediated facilitation of glutamate release at multiple hippocampal synapses by recording IK from presynaptic neurons and evoked AMPA EPSCs at each synapse type of the hippocampus. We will combine pharmacological approaches and knockout mice to determine the involved intracellular signaling molecules. Specific Aim 2 will determine the cellular and molecular mechanisms underlying CCK-mediated enhancement of NMDA currents. We will test the hypothesis that CCK enhances whole-cell NMDA currents by increasing both the membrane expression and the function of NMDA receptors. We will perform electrophysiological and immunocytochemical measurements of CCK-induced increases in membrane expression of NMDA receptors. Specific Aim 3 will determine the cellular and molecular mechanisms of CCK in anxiety. We will test the hypothesis that the functions of PLC and PKC are involved in CCK-mediated anxiogenic effects using two animal anxiety models (Elevated plus maze and Vogel Conflict test). We believe that determination of the mechanisms underlying CCK-mediated anxiogenic effects would contribute significantly to the therapy of anxiety disorders. PUBLIC HEALTH RELEVANCE: Anxiety disorders are among the most common psychiatric disorders and affect about 20 million American people. Cholecystokinin (CCK) system in the brain has long been known to underlie the pathogenesis of anxiety. However, the molecular and cellular mechanisms whereby CCK facilitates anxiety remain unsolved. Because elevation in glutamatergic functions underlies the generation of anxiety, we have examined the effects of CCK on glutamatergic functions in the hippocampus, an important limbic structure that is involved in controlling mood and emotion. We have substantial preliminary data demonstrating that CCK increases glutamate release at multiple synapses of the hippocampus. We have also shown that CCK increases NMDA type of glutamate receptor-mediated currents in isolated hippocampal neurons. Using two animal anxiety models (Elevated plus maze and Vogel Conflict test), we demonstrated that CCK-induced increase in anxiety is mediated via ionotropic glutamate receptors. The overall objective of this application is to determine the involved detailed cellular and molecular mechanisms by testing the hypothesis that CCK-induced increase in glutamatergic function is responsible for its anxiogenic effects. We believe that determination of the mechanisms underlying CCK-mediated anxiogenic effects would contribute significantly to the therapy of anxiety disorders.

描述（由申请人提供）：焦虑是美国最普遍的精神疾病之一，目前影响到约2000万人。目前可用的抗焦虑药，虽然有些有效，但有副作用，并针对有限数量的机制。探索治疗焦虑的新机制或策略仍然是一项艰巨的任务。尽管大量研究表明胆囊收缩素（CCK）系统在焦虑的发病机制中起着重要作用，但其细胞和分子机制仍不清楚。由于海马神经元功能的升高是焦虑产生的基础，我们研究了CCK对海马神经元传递的影响，海马神经元是一种密切参与上下文相关信息处理和对环境信号的焦虑反应表达的结构。我们有大量的初步数据表明，CCK通过抑制延迟整流钾通道（IK）增加谷氨酸释放在海马的多个突触。我们还发现，CCK增加NMDA型谷氨酸受体介导的电流在分离的海马神经元。CCK对谷氨酸释放和NMDA受体功能的影响是通过CCK-2受体介导的，并需要磷脂酶C（PLC）和蛋白激酶C（PKC）的作用。使用两种动物焦虑模型（高架十字迷宫和Vogel冲突测试），我们证明了CCK诱导的焦虑增加是通过离子型谷氨酸受体介导的。本项目的目的是通过检验CCK诱导的多巴胺能功能增加是其致焦虑作用的原因这一假设来确定所涉及的详细的细胞和分子机制。具体目标1将确定详细的离子和信号转导机制CCK介导的促进谷氨酸释放在多个海马突触记录IK突触前神经元和诱发AMPA EPSC在每个突触类型的海马。我们将结合联合收割机药理学方法和基因敲除小鼠来确定所涉及的细胞内信号分子。具体目标2将确定CCK介导的NMDA电流增强的细胞和分子机制。我们将检验CCK通过增加NMDA受体的膜表达和功能来增强全细胞NMDA电流的假设。我们将进行电生理和免疫细胞化学测量CCK诱导的NMDA受体的膜表达增加。具体目标3将确定CCK在焦虑中的细胞和分子机制。我们将使用两种动物焦虑模型（高架迷宫和Vogel冲突测试）来检验PLC和PKC的功能参与CCK介导的焦虑效应的假设。我们相信，CCK介导的焦虑作用的机制的确定将有助于显着的焦虑症的治疗。公共卫生相关性：焦虑症是最常见的精神疾病之一，影响约2000万美国人。脑中的胆囊收缩素（CCK）系统长期以来被认为是焦虑症发病机制的基础。然而，CCK促进焦虑的分子和细胞机制仍然没有解决。由于海马神经功能的升高是焦虑产生的基础，我们研究了CCK对海马神经功能的影响，海马是一个重要的边缘系统结构，参与控制情绪和情感。我们有大量的初步数据表明，胆囊收缩素增加谷氨酸释放在多个突触的海马。我们还发现，CCK增加NMDA型谷氨酸受体介导的电流在分离的海马神经元。使用两种动物焦虑模型（高架十字迷宫和Vogel冲突测试），我们证明了CCK诱导的焦虑增加是通过离子型谷氨酸受体介导的。本申请的总体目标是通过检验CCK诱导的多巴胺能功能增加是其致焦虑作用的原因这一假设，确定所涉及的详细细胞和分子机制。我们相信，CCK介导的焦虑作用的机制的确定将有助于显着的焦虑症的治疗。