Cholecystokinin and anxiety

胆囊收缩素和焦虑

• 批准号: 8249428
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249428
• 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，目前影响约2000万人。当前可用的抗焦虑药虽然有效，但具有副作用，并针对有限的机制。探索新颖的机制或治疗焦虑的策略仍然是一项艰巨的任务。尽管巨大的研究表明胆囊动蛋白（CCK）系统在焦虑发病机理中的重要作用，而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，因此我们检查了CCK对海马中谷氨酸能传播的影响，这是一种与上下文相关信息处理的结构以及对环境信号的焦虑反应的表达。我们有大量的初步数据，表明CCK通过抑制延迟的整流器K+通道（IK）来增加海马多个突触处的谷氨酸释放。我们还表明，CCK增加了分离的海马神经元中NMDA类型的谷氨酸受体介导的电流。 CCK对谷氨酸释放和NMDA受体功能的影响是由CCK-2受体介导的，需要磷脂酶C（PLC）和蛋白激酶C（PKC）的功能。使用两个动物焦虑模型（升高的迷宫和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。该项目的目的是通过测试CCK诱导的谷氨酸能功能增加的假设来确定所涉及的详细细胞和分子机制，这是其焦虑作用的原因。特定的目标1将通过记录来自海马的每种突触类型的AMPA EPSC的IK来确定CCK介导的在多个海马突触下谷氨酸释放的详细离子和信号传导机制。我们将结合药理学方法和敲除小鼠，以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。我们将测试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测量。具体目标3将确定CCK焦虑中CCK的细胞和分子机制。我们将检验以下假设：PLC和PKC的功能使用两种动物焦虑模型（升高的迷宫和Vogel冲突测试）参与CCK介导的抗焦虑作用。我们认为，确定CCK介导的抗焦虑作用的机制将对焦虑症的治疗产生重大贡献。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。长期以来，大脑中的胆囊动蛋白（CCK）系统是焦虑发病机理的基础。但是，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，因此我们研究了CCK对海马谷氨酸谷氨酸能功能的影响，这是一种重要的边缘结构，涉及控制情绪和情感。我们有大量的初步数据，表明CCK在海马多个突触下增加了谷氨酸释放。我们还表明，CCK在分离的海马神经元中增加了NMDA类型的谷氨酸受体介导的电流。使用两个动物焦虑模型（升高的迷宫和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。该应用的总体目的是通过测试CCK诱导的谷氨酸能功能增加的假设来确定所涉及的详细细胞和分子机制，这是其焦虑作用的原因。我们认为，确定CCK介导的抗焦虑作用的机制将对焦虑症的治疗产生重大贡献。