Modelling the effect of V1a receptor antagonism and its potential therapeutic effect in circadian disorders

The suprachiasmatic nucleus (SCN) is the central circadian clock in mammals, and its dysregulation is linked to various circadian disorders. Vasopressin signaling is a primary regulator of SCN synchronicity and functional output. We investigated the effect of the V1a receptor (V1aR) antagonist, balovaptan (30 mg/kg), on locomotor activity rhythms in mice following a 6-hour phase advance of the light-dark cycle. We found that a single administration significantly accelerated resynchronization of locomotor rhythms. To investigate the underlying mechanism, we developed a mathematical framework simulating the SCN and its control of biomarkers, including melatonin and core body temperature. Our model successfully captures the accelerated synchronization observed under V1aR antagonism and replicates well-established SCN behaviors, such as the phase response curve and forced desynchronization. Mechanistically, the model suggests that weakening vasopressin signaling strengthens the SCN's resistance to internal desynchronization. Furthermore, we show a strong link between the endogenous period and the phase of circadian biomarkers. The model predicts that V1aR antagonism induces a phase advance proportional to the endogenous period, suggesting that individuals with longer endogenous periods may experience more substantial therapeutic benefits. This framework establishes a computational foundation for designing clinical trials evaluating V1aR antagonism for circadian rhythm disorders.