title: Molecular mechanism regulating 24-hour rhythm of dopamine D3 receptor expression in mouse ventral striatum.
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 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 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 REV-ERBα 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 RORα and REV-ERBα consist of a reciprocating mechanism wherein RORα 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.
authors: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors: Eriko
authors: E
authors: Ikeda
authors: Naoya
authors: N
authors: Matsunaga
authors: Keisuke
authors: K
authors: Kakimoto
authors: Kengo
authors: K
authors: Hamamura
authors: Akane
authors: A
authors: Hayashi
authors: Satoru
authors: S
authors: Koyanagi
authors: Shigehiro
authors: S
authors: Ohdo
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation / Q000379:methods; D002940:Circadian Rhythm / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D041681:NIH 3T3 Cells; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C493594:Drd3 protein, mouse; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; D050637:Receptors, Dopamine D3; C539739:Rora protein, mouse; D013764:Tetrahydronaphthalenes; D003907:Dexamethasone; C031349:7-hydroxy-2-N,N-dipropylaminotetralin