Dopamine receptor D3 affects the expression of Period1 in mouse cells via DRD3–ERK–CREB signaling

Circadian rhythm alterations are related to the onset and severity of various diseases. The expression of the dopamine receptor D3 (DRD3) is regulated by clock genes, and DRD3 functional abnormalities are linked to various neurological diseases. However, the relationship between DRD3 function and circadian machinery is unclear. Here, we demonstrate the influence of DRD3 on the circadian machinery. Although the expression of DRD3 in mouse suprachiasmatic nucleus (SCN) did not show a circadian rhythm, the expression of Per1 mRNA was altered in the SCN of Drd3 knockout (Drd3^−/−) mice compared to that in wild-type (WT) mice. These differences were caused by the upregulation of the DRD3–extracellular signal–regulated kinase–cAMP response element binding protein (DRD3–ERK–CREB) signaling pathway in cultured cells and SCN. In addition, Drd3^−/− mice demonstrated increased period length of locomotor activity than WT mice only under constant dark conditions. Expression of clock genes in the liver, which does not express DRD3, was affected by the loss of DRD3 only under constant dark conditions, similar to that in the SCN. These results suggest that DRD3 expressed in the SCN regulates the central clock via endogenous ligands and affects peripheral organs. This may provide new evidence to unravel the relationship between dopamine neurotransmission and the circadian clock, which has not yet been fully elucidated.