Molecular mechanism regulating 24-hour rhythm of dopamine D3 receptor expression in mouse ventral striatums

Eriko Ikeda, Naoya Matsunaga, Keisuke Kakimoto, Kengo Hamamura, Akane Hayashi, Satoru Koyanagi, Shigehiro Ohdo

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

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 a (RORa), and its activation was inhibited by the orphan receptor REV-ERBα, an endogenous antagonist of RORa. The serum or dexamethasone-induced oscillation in the expression of DRD3 in cells was abrogated by the downregulation or overexpression of REV-ERBα, suggesting that REV-ERBα 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 REVERBα 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-OHDPAT)- induced locomotor hypoactivity were significantly increased when DRD3 proteins were abundant. These results suggest that RORa and REV-ERBα consist of a reciprocating mechanism wherein RORa upregulates the expression of DRD3, whereas REV-ERBα periodically suppresses the expression at the time of day when REV-ERBα 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.

Original languageEnglish
Pages (from-to)959-967
Number of pages9
JournalMolecular Pharmacology
Volume83
Issue number5
DOIs
Publication statusPublished - May 2013

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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