Molecular Mechanism Regulating 24-Hour Rhythm of Dopamine D3 Receptor Expression in Mouse Ventral Striatum

The dopamine D3 receptor (DRD3) in the ventral striatum is thought to influence motivation and motor functions. Although the expression of DRD3 in the ventral striatum has been shown to exhibit 24-hour variations, the mechanisms underlying the variation remain obscure. Here, we demonstrated that molecular components of the circadian clock act as regulators that control the 24-hour variation in the expression of DRD3. The transcription of DRD3was enhanced by the retinoic acid–related orphan receptor α(RORα), and its activation was inhibited by the orphan receptor REV-ERBα, an endogenous antagonist of RORα. The serum or dexamethasone-induced oscillation in the expression of DRD3in cells was abrogated by the downregulation or overexpression of REV-ERBα, suggesting that REV-ERBαfunctions as a regulator of DRD3oscillations in the cellular autonomous clock. Chromatin immunoprecipitation assays of the DRD3promoter indicated that the binding of the REV-ERBαprotein to the DRD3promoter increased in the early dark phase. DRD3 protein expression varied with higher levels during the dark phase. Moreover, the effects of the DRD3 agonist 7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT)–induced locomotor hypoactivity were significantly increased when DRD3 proteins were abundant. These results suggest that RORαand REV-ERBαconsist of a reciprocating mechanism wherein RORαupregulates the expression of DRD3, whereas REV-ERBαperiodically suppresses the expression at the time of day when REV-ERBαis abundant. Our present findings revealed that a molecular link between the circadian clock and the function of DRD3 in the ventral striatum acts as a modulator of the pharmacological actions of DRD3 agonists/antagonists.