Dopamine D3 receptor in the nucleus accumbens alleviates neuroinflammation in a mouse model of depressive-like behavior

•NAc neuroinflammation induced by intra-NAc injection of LPS leads to depressive-like disorders.•NAc neuroinflammation results in D3R expression decline and microglial activation in the NAc.•D3R in the NAc shows a crucial role in the initiation and development of depressive-like behaviors.•D3R inhibition could convert microglia toward a proinflammatory response.•D3R inhibition-induced proinflammatory microglia was primarily through the Akt signaling pathway. We recently reported that dopamine D3 receptor (D3R) was involved in inflammation-related depression. Nucleus accumbens (NAc) inflammation is implicated in the development and progression of depression, but its regulatory mechanism remains largely unknown. In a mouse model of NAc neuroinflammation induced by bilateral NAc injection of lipopolysaccharide (LPS), we observed that NAc neuroinflammation triggered depressive-like behaviors, and D3R expression decline and microglial activation in the NAc. A selective knockdown of D3R in the NAc elicited depressive-like behaviors, while re-expression of D3R in the NAc of global D3RKO mice alleviated depressive-like behaviors induced by D3R deficiency. D3R downregulation in the NAc shifted microglia toward a proinflammatory state, which was validated with cultured mouse microglial cultures. Further in vitro results demonstrated that D3R inhibition induced microglia to enter a proinflammatory state primarily through the Akt signaling pathway. In conclusion, our results suggest that D3R expression in the NAc may inhibit microglial proinflammatory responses in the NAc, thus alleviating NAc neuroinflammation and subsequent depressive-like behaviors through the Akt signaling pathway.