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

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 DRD3 was enhanced by the retinoic acid-related orphan receptor alpha (ROR alpha), and its activation was inhibited by the orphan receptor REV-ERB alpha, an endogenous antagonist of ROR alpha. The serum or dexamethasone-induced oscillation in the expression of DRD3 in cells was abrogated by the downregulation or overexpression of REV-ERB alpha, suggesting that REV-ERB alpha functions as a regulator of DRD3 oscillations in the cellular autonomous clock. Chromatin immunoprecipitation assays of the DRD3 promoter indicated that the binding of the REV-ERB alpha protein to the DRD3 promoter 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 ROR alpha and REV-ERB alpha consist of a reciprocating mechanism wherein ROR alpha upregulates the expression of DRD3, whereas REV-ERB alpha periodically suppresses the expression at the time of day when REV-ERB alpha is 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.