Noradrenergic mechanisms in antidepressant drug effects

描述（由申请方提供）：单胺能神经传递的变化导致行为、情感和认知的时间依赖性改变，包括慢性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，如地昔帕明（DEXPA）。去甲肾上腺素能活性的紧张水平的升高与觉醒、警觉和注意力有关，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，并且去甲肾上腺素能神经传递的阶段性急性应激诱发的激活增强了对应激的焦虑样行为反应。因此，目前尚不清楚如何增强NE传输可能有助于抗焦虑以及抗抑郁作用。尽管如此，选择性NE再摄取抑制剂在解决焦虑相关症状以及抑郁症的抑制症状方面是有效的。因此，在这个项目中，我们假设慢性NE再摄取阻断差异调节紧张性和阶段性激活的去甲肾上腺素能传输，以解释这种双重效应。为了测试这一点，我们提出了一系列的实验，使用微透析，连同一系列的行为药理学研究，以检查时间依赖性的神经化学变化去甲肾上腺素能神经传递，和相应的变化行为措施的注意力转移能力和急性焦虑样行为反应的高架十字迷宫和防御性埋藏测试，慢性治疗后的大鼠与肾上腺素。我们预测，在内侧前额叶皮层的去甲肾上腺素能活性的紧张性升高将增强唤醒和注意力，但同时衰减的阶段，应力激活NE神经传递的边缘系统区域，如床核的终纹和外侧隔通过自身受体介导的抑制，将减少急性焦虑样行为应激反应。还将使用其他选择性NE再摄取抑制剂瑞波西汀和托莫西汀（其缺乏潜在的非选择性突触后拮抗剂活性）验证阿托莫西汀治疗后的关键观察结果。与NIMH的使命相关，更好地了解这些调节过程如何有助于AD药物的抗抑郁和抗焦虑疗效，可能为未来开发更有效，更特异或更快速的治疗提供新的见解，甚至最终预防严重的心理健康问题，如抑郁症和焦虑症。

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.