腹侧被盖区的P2Y1受体调节抑郁样行为

抑郁症是当今世界首要致残因素，但其机制仍不清楚。我们先前研究结果报道星胶来源的ATP缺失调控抑郁样行为。但是，参与其中的受体仍然未知。在此，通过在多个抑郁相关脑区筛选ATP全部受体表达水平改变，我们发现P2Y1受体在抑郁模型鼠的VTA脑区高表达。侧脑室给予P2Y1受体特异性阻断剂后诱导抗抑郁表型。P2Y1全敲小鼠和大鼠均表现出抗抑郁样行为。腹侧被盖区（VTA）特异性激活和抑制P2Y1受体分别产生抗-或 促抑郁样行为。进一步研究发现，VTA多巴胺神经元P2Y1参与抑郁样行为可能通过VTA-NAc通路。以上结果说明VTA脑区的P2Y1参与抑郁的发生发展，可为新型抗抑郁药的研究提供新的研究靶点。

Depression is a major cause of disability worldwide, but the underlying mechanism remains elusive. Our previous study indicates that deficiency of astrocyte-derived ATP modulates depressive-like behaviors. However, the receptors involved are unknown. Here, by screening a series of ATP receptors in multiple depression-related brain regions, we found that the expression of P2Y1 receptors was highly upregulated in the VTA in depressed animals. Central inhibition of P2Y1 receptors reduced depression-like behaviors in normal and socially defeated mice. Both P2Y1 knockout mice and rats showed antidepressant-like behaviors. Inhibition or activation of P2Y1 receptors in the VTA produced anti- or pro-depressive-like effects, respectively. We further showed that P2Y1 receptors on dopamine neurons in the VTA modulated depression-like behaviors via VTA-NAc pathway. These data suggest that P2Y1 receptors in the VTA play an important role in the pathogenesis of depression and may be considered as a novel target for antidepressant.