Noradrenergic mechanisms in antidepressant drug effects

去甲肾上腺素能活动紧张性水平的升高与觉醒、警觉和注意力有关，这可能会改善抑郁症的抑制症状。然而，焦虑也是抑郁的一个重要组成部分，去甲肾上腺素能神经传递的阶段性、急性应激诱发激活增强了焦虑样行为对应激的反应。因此，目前尚不清楚增强NE传递如何有助于缓解焦虑和抗抑郁作用。尽管如此，选择性去甲肾上腺素再摄取抑制剂在解决焦虑相关症状以及抑郁症的抑制性症状方面是有效的。因此，在这个项目中，我们假设慢性去甲肾上腺素再摄取阻断不同地调节紧张性和相性激活的去甲肾上腺素能传递，以解释这种双重效应。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托莫西汀进行验证，这些药物缺乏DMI潜在的非选择性突触后拮抗活性。与NIMH任务相关的是，更好地了解这些调控过程如何有助于AD药物的抗抑郁和抗焦虑疗效，可能会为未来开发更有效、更具体或更快速的治疗方法提供新的见解，甚至最终预防严重的精神健康问题，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.