Department of Psychology & Neuroscience, The University of North Carolina, Chapel Hill, NC, 27599, USA.
Bowles Center for Alcohol Studies, The University of North Carolina, Chapel Hill, NC, 27599, USA.
Neuropsychopharmacology. 2019 May;44(6):1132-1140. doi: 10.1038/s41386-018-0310-7. Epub 2019 Jan 7.
Neuropeptide Y (NPY) signaling via limbic NPY1 and 2 receptors (NPY1R and NPY2R, respectively) is known to modulate binge-like ethanol consumption in rodents. However, the role of NPY signaling in the medial prefrontal cortex (mPFC), which provides top-down modulation of the limbic system, is unknown. Here, we used "drinking-in-the-dark" (DID) procedures in C57BL/6J mice to address this gap in the literature. First, the impact of DID on NPY immunoreactivity (IR) was assessed in the mPFC. Next, the role of NPY1R and NPY2R signaling in the mPFC on ethanol consumption was evaluated through site-directed pharmacology. Chemogenetic inhibition of NPY1R+ neurons in the mPFC was performed to further evaluate the role of this population. To determine the potential role of NPY1R+ neurons projecting from the mPFC to the basolateral amygdala (BLA) this efferent population was selectively silenced. Three, 4-day cycles of DID reduced NPY IR in the mPFC. Intra-mPFC activation of NPY1R and antagonism of NPY2R resulted in decreased binge-like ethanol intake. Silencing of mPFC NPY1R+ neurons overall, and specifically NPY1R+ neurons projecting to the BLA, significantly reduced binge-like ethanol intake. We provide novel evidence that (1) binge-like ethanol intake reduces NPY levels in the mPFC; (2) activation of NPY1R or blockade of NPY2R reduces binge-like ethanol intake; and (3) chemogenetic inhibition of NPY1R+ neurons in the mPFC and NPY1R+ mPFC neurons projecting to the BLA blunts binge-like drinking. These observations provide the first direct evidence that NPY signaling in the mPFC modulates binge-like ethanol consumption.
神经肽 Y（NPY）通过边缘 NPY1 和 2 受体（分别为 NPY1R 和 NPY2R）的信号传递，已知可调节啮齿动物的 binge-like 乙醇消耗。然而，NPY 信号在提供边缘系统的自上而下调节的内侧前额叶皮层（mPFC）中的作用尚不清楚。在这里，我们使用 C57BL/6J 小鼠的“暗饮”（DID）程序来解决文献中的这一空白。首先，评估了 DID 对 mPFC 中 NPY 免疫反应性（IR）的影响。接下来，通过靶向药理学评估了 mPFC 中的 NPY1R 和 NPY2R 信号在乙醇消耗中的作用。进行 mPFC 中 NPY1R+神经元的化学遗传抑制，以进一步评估该群体的作用。为了确定来自 mPFC 投射到基底外侧杏仁核（BLA）的 NPY1R+神经元的潜在作用，选择性地沉默了该传出群体。三个，4 天的 DID 周期减少了 mPFC 中的 NPY IR。mPFC 中 NPY1R 的激活和 NPY2R 的拮抗作用导致 binge-like 乙醇摄入减少。总体而言，沉默 mPFC NPY1R+神经元，特别是投射到 BLA 的 NPY1R+神经元，显著减少了 binge-like 乙醇摄入。我们提供了新的证据，即（1）binge-like 乙醇摄入减少了 mPFC 中的 NPY 水平；（2）激活 NPY1R 或阻断 NPY2R 可减少 binge-like 乙醇摄入；（3）mPFC 中 NPY1R+神经元的化学遗传抑制和投射到 BLA 的 NPY1R+ mPFC 神经元抑制了 binge-like 饮酒。这些观察结果提供了第一个直接证据，表明 mPFC 中的 NPY 信号传递调节 binge-like 乙醇消耗。
