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 a (RORa), and its activation was inhibited by the orphan receptor REV-ERBa, 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-ERBa, suggesting that REV-ERBa 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 REVERBa 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 RORa and REV-ERBa consist of a reciprocating mechanism wherein RORa upregulates the expression of DRD3, whereas REV-ERBa periodically suppresses the expression at the time of day when REV-ERBa 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.

Involvement of dopamine D2 receptor in the diurnal changes of tuberoinfundibular dopaminergic neuron activity and prolactin secretion in female rats

“…Recent studies have shown that striatal D 2 /D 3 R proteins and D 3 R mRNA levels in mouse also exhibit diurnal rhythms [11,12]. Our findings that D 2 R mRNAs in SN and VTA exhibited a morning high, afternoon low rhythm are in agreement with the changes of D 3 R mRNA levels in mouse striatum [12].…”

“…It has been shown that both mouse striatal D 3 R mRNA level [11] and D 2 /D 3 R proteins [12] exhibit diurnal rhythms, which may correlate with motor functions. There is no report, however, on D 2 R mRNA level in medial basal hypothalamus (MBH) where TIDA neurons reside.…”

RNA expression profiling in depressed patients suggests retinoid-related orphan receptor alpha as a biomarker for antidepressant response

“…2,47 The physiological meaning of this finding in depression remains unclear, but may point to adaptive changes in nonresponders. The idea of adaptive processes may be indirectly supported by the recent finding of Ikeda et al 48 who showed that RORa upregulates expression of dopamine D3 receptor (DRD3) in mice ventral striatum. This interpretation is in line with restored dopaminergic signaling that has been implicated in recovery from depression.…”

Minutes, days and years: molecular interactions among different scales of biological timing

“…There is also evidence that indicate the regulation of DA receptors by circadian clock proteins in the striatum. In this sense, a 24 h rhythm in the expression of the DA D3 receptor was recently described, which is enhanced by RORa and inhibited by Rev-Erba [139]. Moreover, a recent study [140] in humans suggested that a polymorphism in the PER2 protein correlates with striatal D2 receptor availability.…”