Jensen Morten, Ratner Cecilia, Rudenko Olga, Christiansen Søren H, Skov Louise J, Hundahl Cecilie, Woldbye David P D, Holst Birgitte
Laboratory of Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark, and The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark (Mr Jensen, Ms Ratner, Dr Rudenko, Ms Skov, Ms Hundahl, and Dr Holst); Laboratory of Neural Plasticity, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark (Drs Christiansen and Woldbye).
Int J Neuropsychopharmacol. 2016 Apr 29;19(5). doi: 10.1093/ijnp/pyv123. Print 2016 May.
Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has not previously been addressed directly.
First, we examined the acute effect of peripheral ghrelin administration on anxiety- and depression-like behavior using the open field, elevated plus maze, forced swim, and tail suspension tests. Next, we examined the effect of peripheral ghrelin administration and ghrelin receptor deficiency on stress in a familiar and social environment using the Intellicage system. Importantly, we also used a novel approach to study ghrelin receptor signaling in the brain by overexpressing the ghrelin receptor in the amygdala. We examined the effect of ghrelin receptor overexpression on anxiety-related behavior before and after acute stress and measured the modulation of serotonin receptor expression.
We found that ghrelin caused an anxiolytic-like effect in both the open field and elevated plus maze tests. Additionally, it attenuated air-puff-induced stress in the social environment, while the opposite was shown in ghrelin receptor deficient mice. Finally, we found that overexpression of the ghrelin receptor in the basolateral division of the amygdala caused an anxiolytic-like effect and decreased the 5HT1a receptor expression.
Ghrelin administration and overexpression of the ghrelin receptor in the amygdala induces anxiolytic-like behavior. Since the ghrelin receptor has high constitutive activity, ligand-independent signaling in vivo may be important for the observed anxiolytic-like effects. The anxiolytic effects seem to be mediated independently from the HPA axis, potentially engaging the central serotonin system.
除了胃饥饿素对肥胖和食物摄入调节的众所周知的作用外，胃饥饿素系统还被证明可调节包括焦虑和应激在内的行为方面。然而，此前尚未直接探讨病毒介导的杏仁核中胃饥饿素受体过表达的影响。
首先，我们使用旷场试验、高架十字迷宫试验、强迫游泳试验和悬尾试验，研究外周给予胃饥饿素对焦虑样和抑郁样行为的急性影响。接下来，我们使用智能笼系统，研究外周给予胃饥饿素和胃饥饿素受体缺乏对熟悉和社交环境中应激的影响。重要的是，我们还采用了一种新方法，通过在杏仁核中过表达胃饥饿素受体来研究其在大脑中的信号传导。我们研究了急性应激前后胃饥饿素受体过表达对焦虑相关行为的影响，并测量了5-羟色胺受体表达的调节情况。
我们发现，胃饥饿素在旷场试验和高架十字迷宫试验中均产生抗焦虑样作用。此外，它减轻了社交环境中吹气诱导的应激，而胃饥饿素受体缺陷小鼠则表现出相反的情况。最后，我们发现杏仁核基底外侧核中胃饥饿素受体的过表达产生了抗焦虑样作用，并降低了5HT1a受体的表达。
给予胃饥饿素和在杏仁核中过表达胃饥饿素受体可诱导抗焦虑样行为。由于胃饥饿素受体具有较高的组成性活性，体内不依赖配体的信号传导可能对观察到的抗焦虑样作用很重要。抗焦虑作用似乎独立于下丘脑-垂体-肾上腺轴介导，可能涉及中枢5-羟色胺系统。
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