To study the relationship between the expression of specific P2X2 receptor of ATP and occurrence of syndrome of liver depression and spleen deficiency, in order to lay the foundation for the study on relationship between the release phenomenon of ATP and occurrence of syndrome of liver depression and spleen deficiency. Methods:A total of 48 C57BL/6J mice were randomly divided into 4 groups as normal group, model group, Xiaoyaosan group, and Fluoxetine group. All the mice, except the normal group, received multiple stresses for 21 days to establish the mice model of syndrome of liver depression and spleen deficiency. Immunohistochemical technique, Western blot, and qPCR were used to test the expression of protein and mRNA of P2X2 receptor in prefrontal cortex of mice. Results:Compared with the normal group, the expression of protein of P2X2 receptor of mice in model group decreased significantly (P<0.05), and the expression of mRNA of P2X2 receptor of mice in model group declined, although it was not significant (P>0.05). Compared with model group, the expression of protein of P2X2 receptor of mice in Xiaoyaosan and Fluoxetine groups increased significantly (P<0.05), and the expression of mRNA of P2X2 receptor of mice in Fluoxetine group also increased (P<0.05). Conclusion:Induced by multiple stresses, the expression of P2X2 receptor in prefrontal cortex of mice with syndrome of liver depression and spleen deficiency tends to be reduced, which might be an important reason of occurrence of syndrome of liver depression and spleen deficiency.