Credit: NPG

The molecular underpinnings that cause jet lag are unclear. Now, Okamura and colleagues report that the arginine vasopressin (AVP) receptor subtypes V1A and V1B are key players for synchronizing the internal circadian clock with the environmental light–dark cycle.

The suprachiasmatic nucleus (SCN) in the brain is dubbed the master clock of internal circadian rhythms, and using a histochemistry-based screening strategy the authors first showed that expression levels of AVP as well as the V1A and V1B receptors were particularly high in this brain region. Next, they went on to examine the behaviour and expression patterns of selected circadian clock genes in the SCN of mice deficient in both of these receptors (Avpr1a−/−Avpr1b−/− mice) under normal and jet-lag-simulated conditions. For 2 weeks, wild-type mice and Avpr1a−/−Avpr1b−/− mice were housed in conditions of 12-hour light and 12-hour dark cycles. After this, jet lag was simulated by advancing the light–dark cycle by 8 hours.

Before jet lag was induced, both types of mice were equally active during the dark phase, indicating that the absence of the V1A and V1B receptors in mice did not lead to overt differences in behaviour. In addition, expression of the canonical circadian clock genes (Per1, Per2, Bma1 and Dbp) in the SCN was similar between wild-type and Avpr1a−/−Avpr1b−/− mice. After jet lag was induced, it took wild-type mice 8–10 days to synchronize the time when they became active to the actual time when the dark phase began (that is, to re-entrain). In Avpr1a−/−Avpr1b−/− mice, re-entrainment took 2–4 days. Moreover, in wild-type mice, expression of Per1, Per2, Bma1 and Dbp took 8–9 days to return to the original circadian rhythm of expression, whereas it took 3 days in Avpr1a−/−Avpr1b−/− mice.

Interestingly, the increased rapidity at which Avpr1a−/−Avpr1b−/− mice re-entrained after jet lag could be pharmacologically induced in wild-type mice. Administration of a mixture containing a V1A receptor antagonist (OPC-21268) and a V1B receptor antagonist (SSR 149415) directly into the SCN of wild-type mice through an osmotic minipump led to faster re-entrainment to new light–dark cycles in a dose-dependent manner.

Together, these data suggest that V1A and V1B receptors could be therapeutic targets for treating altered circadian rhythms such as jet lag or rotating shift work.