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

Abstract

BackgroundThe suprachiasmatic nucleus (SCN) is the central circadian clock in mammals, regulating many daily physiological and behavioral rhythms. Dysregulation of the SCN is associated with various circadian disorders, highlighting the potential therapeutic benefits of targeting its neurons and output pathways. Vasopressin signaling is one of the main regulators of the synchronicity and the functional output of the SCN. MethodsWe investigated the effect of a single dose (30mg/kg) of the vasopressin V1a receptor (V1aR) antagonist, balovaptan, on resynchronization of locomotor activity rhythms in mice after a 6-hour phase advance of the light-dark cycle. To mechanistically model the effect of V1aR antagonism, we developed a mathematical framework simulating the SCN, its control of circadian biomarkers (melatonin, core body temperature), and the impact of V1aR antagonism. ResultsA single administration of the V1a antagonist balovaptan significantly accelerated resynchronization of locomotor activity rhythms to new light-dark cycles. To mechanistically understand this effect, we devised a mathematical model of the SCN that successfully captures this accelerated synchronization of circadian rhythms under V1aR antagonism. Additionally, the model replicates well-established SCN behaviors in both humans and rodents, including the phase response curve triggered by a light pulse at various circadian phases, and the desynchronization of the SCN observed in forced desynchronization experiments. Mechanistically, our model suggests that weakening vasopressin signaling via V1aR antagonism strengthens the SCNs resistance to internal desynchronization. Additionally, our model suggests a strong link between the endogenous period (tau) and the phase of circadian biomarkers, with longer tau values resulting in delayed biomarker rhythms. Importantly, the model predicts that V1aR antagonism induces a phase advance proportional to tau. The model predicts that individuals with longer endogenous periods, who consequently exhibit greater phase delays in their circadian rhythms, could experience more substantial phase advances in response to V1aR antagonism. DiscussionWe show that targeting V1aR is enough to cause a faster resynchronization to a new light-dark cycle in the jet lag paradigm and establish a computational framework for investigating its therapeutic potential in circadian rhythm disorders. This framework, adaptable to incorporate pharmacodynamic data, can be used to design clinical trials evaluating V1aR antagonism for treating circadian disorders.