Noradrenergic mechanisms in antidepressant drug effects

抗抑郁药物作用中的去甲肾上腺素能机制

• 批准号: 7394417
• 负责人: David A Morilak
• 金额: $ 30.13万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-05 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394417
• 关键词: Accounting; Acute; Address; Adrenergic Agents; Adrenergic Antagonists; Affect; Aggressive behavior; Agitation; Agonist; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Arousal; Attention; Attenuated; Autoreceptors; Behavior; Behavioral; Bispecific Antibody 2B1; Chronic; Clonidine; Cognition; Cognitive; Comorbidity; Depressed mood; Desipramine; Development; Diagnosis; Distress; Elevation; Emotional; Future; Generations; Immobilization; Lateral; Measures; Medial; Mediating; Mental Depression; Mental Health; Microdialysis; Microinjections; Mission; Modification; National Institute of Mental Health; Norepinephrine; Patients; Performance; Pharmaceutical Preparations; Prefrontal Cortex; Prevention; Principal Investigator; Process; Rattus; Research; Research Personnel; Role; Series; Shock; Stress; Structure of terminal stria nuclei of preoptic region; Symptoms; Synapses; Testing; Time; Upper arm; Withdrawal; acute stress; adrenergic; atipamezole; atomoxetine; attenuation; behavior measurement; biological adaptation to stress; cognitive function; depressive symptoms; extracellular; improved; indexing; inhibitor/antagonist; insight; neurochemistry; neurotransmission; noradrenergic; novel; programs; reboxetine; research study; response; reuptake; social; transmission process; vigilance

DESCRIPTION (provided by applicant): Changes in monoaminergic neurotransmission contribute to time-dependent modifications in behavior, affect and cognition that comprise both the antidepressant and anxiolytic effects of chronic antidepressant drug treatment, including selective norepinephrine (NE) reuptake inhibitors such as desipramine (DMI). Elevation of tonic levels of noradrenergic activity has been implicated in arousal, vigilance, and attention, which could improve inhibitory symptoms of depression. However, anxiety is also a prominent component of depression, and phasic, acute stress-evoked activation of noradrenergic neurotransmission enhances anxiety-like behavioral responses to stress. Therefore, it is unclear how enhancing NE transmission could contribute to anxiolytic as well as antidepressant effects. Nonetheless, selective NE reuptake inhibitors are effective in resolving anxiety-related symptoms as well as inhibitory symptoms of depression. Thus, in this project, we hypothesize that chronic NE reuptake blockade differentially regulates tonic- and phasically-activated noradrenergic transmission to account for this dual effect. To test this, we propose a series of experiments using microdialysis, together with a series of behavioral pharmacological studies, to examine time-dependent neurochemical changes in noradrenergic neurotransmission, and corresponding changes in behavioral measures of attentional set-shifting capability and acute anxiety-like behavioral reactivity on the elevated plus-maze and defensive burying tests, after chronic treatment of rats with DMI. We predict that tonically elevating noradrenergic activity in the medial prefrontal cortex will enhance arousal and attention, but that a concurrent attenuation of phasic, stress-activated NE neurotransmission in limbic regions such as the bed nucleus of the stria terminalis and lateral septum via autoreceptor-mediated inhibition, will reduce acute anxiety-like behavioral stress reactivity. Key observations made following DMI treatment will also be verified using other selective NE reuptake inhibitors, reboxetine and atomoxetine, which lack the potential non- selective post-synaptic antagonist activity of DMI. Relevant to the NIMH mission, a better understanding of how these regulatory processes contribute to both antidepressant and anxiolytic efficacy of AD drugs may offer novel insights for future development of more effective, more specific or more rapid treatment, or even ultimately to the prevention of serious mental health problems such as depression and anxiety disorders.

描述（由申请人提供）：单胺能神经传递的变化有助于行为，情感和认知的时间依赖性修饰，构成了慢性抗抑郁药物治疗的抗抑郁药和抗焦虑作用，包括选择性去甲肾上腺素（NE）抑制剂，例如desipramine（例如DMI）。促甲肾上腺素活性水平的升高与唤醒，警惕和注意力有关，这可以改善抑郁症的抑制症状。然而，焦虑也是抑郁症的重要组成部分，以及急性压力引起的甲肾上腺素能神经递质激活增强了对压力的焦虑样行为反应。因此，尚不清楚增强NE传播如何有助于抗焦虑和抗抑郁作用。但是，选择性的NE再摄取抑制剂在解决与焦虑有关的症状以及抑郁症状的抑制症状方面有效。因此，在这个项目中，我们假设慢性NE重新摄取阻断了差异化调节强调和源动激活的去甲肾上腺素能传播，以解释这种双重效应。为了进行测试，我们提出了一系列使用微透析的实验，以及一系列行为药理研究，以检查与时间有关的神经化神经传递的神经化学变化，以及对高度抗衡的测试的注意力和急性焦虑能力的行为度量的相应变化，以及急性焦虑症的行为反应，并在高度术中进行了防御性测试。我们预测，内侧前额叶皮层中的甲肾上腺素能活性升高将增强唤醒和注意力，但同时衰减是在边缘区域的相位，压力激活的NE神经转移区域中的神经转移，例如质状末端的床核，以及通过自身触发压力反应症状的肌肉反应症状，将使肌肉反应症状敏感性刺激性刺激性。在DMI处理后进行的主要观察结果还将使用其他选择性的NE再摄取抑制剂，再辅助蛋白和阿托莫西汀进行验证，这些抑制剂缺乏潜在的非选择性的DMI突触后拮抗剂活性。与NIMH任务相关，对这些监管过程如何有助于AD药物的抗抑郁药和抗焦虑功效，可以为未来的开发提供新的见解，以实现更有效，更具体或更快速的治疗，甚至最终导致预防严重的精神健康问题，例如抑郁症和焦虑症等严重的精神疾病。