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: 7070240
• 负责人: David A Morilak
• 金额: $ 31.03万
• 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/7070240
• 关键词: antiadrenergic agents; antidepressants; anxiety; arousal; attention; behavior test; desipramine; laboratory rat; microdialysis; microinjections; neural transmission; neurotransmitter transport; norepinephrine; prefrontal lobe /cortex; psychopharmacology; stress

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改变，包括长期抗抑郁药物治疗的抗抑郁和抗焦虑作用，包括选择性去甲肾上腺素（NE）再摄取抑制剂，例如地昔帕明（DMI） ）。去甲肾上腺素能活性的强直水平升高与唤醒、警惕和注意力有关，这可以改善抑郁症的抑制症状。然而，焦虑也是抑郁症的一个重要组成部分，并且阶段性、急性压力诱发的去甲肾上腺素能神经传递激活增强了对压力的焦虑样行为反应。因此，目前尚不清楚增强 NE 传输如何有助于抗焦虑和抗抑郁作用。尽管如此，选择性 NE 再摄取抑制剂可有效解决焦虑相关症状以及抑郁症的抑制症状。因此，在这个项目中，我们假设慢性 NE 再摄取阻断差异性地调节强直性和阶段性激活的去甲肾上腺素能传递，以解释这种双重效应。为了测试这一点，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学研究，以检查去甲肾上腺素能神经传递的时间依赖性神经化学变化，以及注意力转移能力和急性焦虑样行为测量的相应变化DMI 大鼠长期治疗后，高架十字迷宫和防御性掩埋测试的行为反应。我们预测，内侧前额叶皮质中去甲肾上腺素能活性的紧张性升高将增强唤醒和注意力，但通过自身受体介导，边缘区域（例如终纹床核和侧隔）的阶段性、应激激活的 NE 神经传递会同时减弱。抑制，会减少急性焦虑样行为应激反应。 DMI 治疗后的关键观察结果也将使用其他选择性 NE 再摄取抑制剂瑞波西汀和阿托西汀进行验证，这些抑制剂缺乏 DMI 潜在的非选择性突触后拮抗剂活性。与 NIMH 的使命相关，更好地了解这些监管过程如何有助于 AD 药物的抗抑郁和抗焦虑功效，可能会为未来开发更有效、更特异或更快速的治疗方法，甚至最终预防严重的 AD 药物提供新的见解。心理健康问题，例如抑郁症和焦虑症。