Dopamine D3 receptor mediates natural and methamphetamine rewards via regulating the expression of miR-29c in the nucleus accumbens of mice

The dopamine D3 receptor (D3R), principally confined to the nucleus accumbens (NAc), is involved in regulating natural and drug rewards; however, the molecular mechanisms underlying the associated process remain unclear. Earlier research has reported the concurrent influence of D3R and miR-29c expressed in the NAc on methamphetamine (METH)-induced reward behaviors and microglial activation, hinting at regulatory roles in reward processing. Herein, we performed viral manipulation-mediating D3R/miR-29c overexpression and inhibition in the whole NAc in male D3R knockout and wild-type mice to investigate this potential relationship. Behavioral responses to the rewarding stimuli were assessed using sucrose preference score, METH-induced locomotor sensitization, and METH-induced conditioned place preference tests. Overall, we observed a notable decrease in the behavioral response to sucrose and METH in D3R-deficient mice, accompanied by the downregulation of miR-29c expression in the NAc. Diminished responses to those rewarding stimuli in D3R-deficient mice primarily stemmed from the reduction of GSK3β activity and subsequent down-regulation of miR-29c in the NAc. Microglial activation in the NAc mediates the effect of D3R-miR-29c deficiency on the reward effects of sucrose and METH. Pharmacological suppression of microglial activity rescued the reduced response in mice lacking D3R-miR-29c in the NAc. Overall, this study revealed the mechanism by which D3R regulates both natural and drug rewards via miR-29c in the murine NAc, highlighting the role of the NAc D3R-miR-29c pathway as a critical regulator of rewards, and providing new insights into the role of NAc D3R-miR-29c in encoding rewarding experiences.