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(申请人提供)：焦虑症是美国最普遍的精神疾病之一，目前影响约2000万人。目前可用的抗焦虑药物，虽然有些有效，但也有副作用，而且针对的机制有限。探索治疗焦虑的新机制或策略仍然是一项艰巨的任务。大量研究表明，CCK系统在焦虑症的发病机制中起着重要作用，但其潜在的细胞和分子机制仍未解决。由于谷氨酸能功能的升高是焦虑产生的基础，我们研究了CCK对海马区谷氨酸能传递的影响，海马区是一个密切参与背景相关信息处理和焦虑反应对环境信号表达的结构。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)，增加了海马区多个突触的谷氨酸释放。我们还发现CCK增加了分离的海马神经元上NMDA型谷氨酸受体介导的电流。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，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(提升加迷宫和Vogel冲突测试)，我们证明CCK诱导的焦虑增加是通过离子型谷氨酸受体介导的。这个项目的目的是通过检验CCK诱导的谷氨酸能功能增加是其焦虑效应的原因这一假说来确定涉及的详细的细胞和分子机制。具体目标1将通过记录突触前神经元的IK和在每个突触类型上诱发的AMPA EPSCs来确定CCK介导的促进多个海马突触的谷氨酸释放的详细离子和信号机制。我们将结合药理学方法和基因敲除小鼠来确定相关的细胞内信号分子。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。我们将验证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。我们将对CCK诱导的NMDA受体膜表达增加进行电生理和免疫细胞化学检测。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)来验证PLC和PKC功能参与CCK介导的焦虑效应的假设。我们相信，确定CCK介导的焦虑效应的潜在机制将对焦虑症的治疗有重要意义。公共卫生相关性：焦虑症是最常见的精神障碍之一，影响着大约2000万美国人。长期以来，大脑中的CCK系统一直被认为是焦虑症发病的基础。然而，CCK促进焦虑的分子和细胞机制仍未解决。由于谷氨酸能功能的升高是焦虑产生的基础，我们研究了CCK对海马区谷氨酸能功能的影响，海马区是一种重要的边缘结构，参与控制情绪和情绪。我们有大量的初步数据表明，CCK增加了海马区多个突触的谷氨酸释放。我们还发现CCK增加了海马神经元上NMDA型谷氨酸受体介导的电流。使用两种动物焦虑模型(提升加迷宫和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。这项应用的总体目标是通过检验CCK诱导的谷氨酸能功能增加是其焦虑效应的原因这一假设来确定涉及的详细的细胞和分子机制。我们相信，确定CCK介导的焦虑效应的潜在机制将对焦虑症的治疗有重要意义。