Tonic dopamine sensing reveals a D2 and D3-mediated dopamine response to raclopride in ClockΔ19 mice model

The circadian rhythm regulates physiological and behavioral processes, with disruptions linked to metabolic and neuropsychiatric disorders. Circadian genes play a crucial role in the regulation of dopaminergic signaling, yet the underlying molecular mechanisms remain unclear. This study investigates how the Clock gene modulates dopamine (DA) dynamics using in vivo electrochemical DA sensing and molecular profiling. Utilizing carbon fiber electrodes (CFEs) with poly(3,4-ethylenedioxythiophene)/carbon nanotube (PEDOT/CNT) coatings, we measured extracellular DA levels in the striatum of wild-type (WT) and ClockΔ19 mutant mice via square wave voltammetry (SWV). Pharmacological perturbation with raclopride (D2/D3 receptor antagonist) and nomifensine (DA reuptake inhibitor) revealed an increased DA receptor sensitivity in ClockΔ19 mice, with a significantly faster DA response to raclopride. Molecular profiling via qRT-PCR showed elevated tyrosine hydroxylase (TH) expression in the ventral tegmental area (VTA) of ClockΔ19 mice, suggesting increased DA synthesis. Additionally, ClockΔ19 mice exhibited higher expression of D2 DA receptors and glutamate decarboxylase 67 (Gad67) in the VTA and of D3 DA receptors in the nucleus accumbens (NAc), implicating altered dopaminergic and γ-aminobutyric acid (GABA)ergic regulation. These findings highlight the Clock gene's role in DA homeostasis, revealing its impact on neurotransmission.