Neurosciences Centre for Excellence in Drug Discovery, Mood and Anxiety Disorders DPU, GlaxoSmithKline Medicines Research Center, via Fleming 4, 37135 Verona, Italy.
Neuroscience. 2011 Mar 10;176:420-30. doi: 10.1016/j.neuroscience.2010.10.075. Epub 2010 Nov 3.
Neuropeptide Y (NPY) has been extensively studied in relation to anxiety and depression but of the seven NPY receptors known to date, it is not yet clear which one is mainly involved in mediating its effects in emotional behavior. Mice lacking the NPY-Y2 receptors were previously shown to be less anxious due to their improved ability to cope with stressful situations. In the present study, the behavioral phenotype including the response to challenges was analyzed in NPY-Y2 knockout (KO) mice backcrossed in to congenic C57BL/6 background. In the elevated plus-maze (EPM) and the forced swim test (FST), the anxiolytic-like or antidepressant-like phenotype of the NPY-Y2 KO mice could not be confirmed, although this study differs from the previous one only with regard to the genetic background of the mice. In addition, no differences in response to acute stress or to the antidepressant desipramine in the FST were detected between wild type (WT) and NPY-Y2 KO animals. These results suggest that the genetic background of the animals appears to have a strong influence on the behavioral phenotype of NPY-Y2 KO mice. Additionally, to further characterize the animals by their biochemical response to a challenge, the neurochemical changes induced by the anxiogenic compound yohimbine were measured in the medial prefrontal cortex (mPFC) of NPY-Y2 KO and compared to WT mice. Dopamine (DA) levels were significantly increased by yohimbine in the WT but unaffected in the KO mice, suggesting that NPY-Y2 receptor exerts a direct control over both the tonic and phasic release of DA and that, although the anxiety-like behavior of these NPY-Y2 KO mice is unaltered, there are clear modifications of DA dynamics. However, yohimbine led to a significant increase in noradrenaline (NA) concentration and a slight reduction in serotonin concentration that were identical for both phenotypes.
神经肽 Y（NPY）在焦虑和抑郁方面的研究已经很广泛，但是到目前为止，已知的 7 种 NPY 受体中，尚不清楚哪种受体主要参与调节其在情绪行为中的作用。以前的研究表明，缺乏 NPY-Y2 受体的小鼠由于其应对应激情况的能力提高而焦虑程度降低。在本研究中，对 NPY-Y2 敲除（KO）小鼠进行了回交以使其在近交 C57BL/6 背景下繁殖，并分析了其行为表型，包括对挑战的反应。在高架十字迷宫（EPM）和强迫游泳试验（FST）中，NPY-Y2 KO 小鼠的抗焦虑样或抗抑郁样表型无法得到证实，尽管这项研究与之前的研究仅在小鼠的遗传背景上有所不同。此外，在 FST 中，WT 和 NPY-Y2 KO 动物对急性应激或抗抑郁药去甲丙咪嗪的反应没有差异。这些结果表明，动物的遗传背景似乎对 NPY-Y2 KO 小鼠的行为表型有很大影响。此外，为了通过对挑战的生化反应进一步对动物进行表征，测量了焦虑化合物育亨宾在 NPY-Y2 KO 和 WT 小鼠的内侧前额叶皮质（mPFC）中引起的神经化学变化。育亨宾使 WT 小鼠的多巴胺（DA）水平显著升高，但 KO 小鼠不受影响，这表明 NPY-Y2 受体对 DA 的紧张性和相发性释放均具有直接控制作用，尽管这些 NPY-Y2 KO 小鼠的焦虑样行为没有改变，但 DA 动力学有明显的改变。但是，育亨宾导致去甲肾上腺素（NA）浓度显著增加，5-羟色胺浓度略有降低，两种表型相同。
