Chronic stimulation of the vpac2 receptor in-vivo lengthens circadian period

Harry Pantazopoulos, PhD

Department of Biology
Northeastern University
Boston, Massachussetts
McLean Hospital, Harvard Medical School
Belmont, Massachussetts

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A number of studies have found that people with depression or bipolar disorder have abnormal circadian rhythms, illustrating a relationship between the sleep/wake cycle and mood.1,2 The present study attempted to elucidate which peptides affect circadian rhythm timing and their potential contributions to sleep and mood. To that end, hamsters were placed in constant darkness for approximately 3 weeks, which allowed the researchers to assess the intrinsic circadian cycles of the animals. Molecular signaling thought to regulate normal circadian rhythms was investigated. One of the signals generated by the suprachiasmatic nucleus (SCN) is mediated by a protein called vasoactive intestinal peptide (VIP). To test whether VIP regulates the circadian rhythm, a VIP receptor (vpac2) agonist was chronically infused into the hamsters’ brains. The agonist lengthened the animals’ circadian duration by approximately 1 hour. Upon discontinuation of agonist administration, the circadian timing returned to normal. Whether this effect was directly mediated by the SCN was tested using SCN-derived cell culture assays. The cell culture study demonstrated that stimulation of the vpac2 receptor lengthened the duration of Period 2 (Per2) gene expression by approximately 1 hour. Per2 is a member of the so-called clock genes, which have been shown to regulate normal circadian rhythms. The results suggest a regulatory relationship between VIP and Per2. This finding is important because approaches that adjust the length of the circadian period by modulating VIP and Per2 signaling may allow clinicians to realign abnormal circadian periods in patients with sleep/wake and mood disorders.

References

Mendlewicz J. Disruption of the circadian timing systems: molecular mechanisms in mood disorders. CNS Drugs. 2009;23(suppl 2):15-26.
Pandi-Perumal SR, Moscovitch A, Srinivasan V, et al. Bidirectional communication between sleep and circadian rhythms and its implications for depression: lessons from agomelatine. Prog Neurobiol. 2009;88:264-271.

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