) lack normal circadian activity, probably because of loss of synchronization among SCN neurons and a loss of rhythmicity in individual cells (2,3,6,8,17,29). Moreover, SCN transplants that are successful in restoring rhythms express VIP (24, 34), suggesting that VIP is a possible SCN output signal.In addition to possible roles in coupling and output, VIP-VIP receptor (VPAC2) signaling may be involved in transduction of photic input to SCN cells. Studies have shown that VIP pulses result in phase delays or phase advances of locomotor activity, depending on circadian time of administration (32). These effects are similar to the phase-shifting effects of light pulses. Electrophysiological investigations have shown that application of VIP, or a VPAC2 receptor agonist, have similar phase-shifting effects on the firing rates of SCN neurons (36). VIP pulses have also been shown to induce expression of the clock genes per1 and per2 (30), similar to the effect of light pulses on per gene expression.Taken together, these findings indicate that VIP mediates several important aspects of circadian rhythm regulation by the SCN. Whereas mice lacking VPAC2 or VIP show either shorter periods or complete loss of rhythmic activity (2, 7), the effect of chronic VPAC2 receptor activation has not been examined. Based on the evidence of a role for VIP-VPAC2 signaling in integrating light information to SCN neurons, together with disruptions in wheelrunning activity and synchrony of SCN neurons in vip Ϫ/Ϫ mice, we hypothesized that chronic stimulation of the VPAC2 receptor may result in lengthening of the period, similar to the effect of constant light (9). In addition, chronic stimulation of the VPAC2 receptor could result in increased or decreased synchrony among SCN cells. If synchrony is decreased, activity rhythms could be disrupted similar to knockout mice. If synchrony is increased, it is expected that the amplitude of a rhythm expressed by a population of rhythmic cells will increase. For example, this might be seen as higher peak expression of a key circadian regulatory gene, per2. Because VIP processes extend outside the SCN, VIP might also act as an output signal from the SCN. If so, chronic stimulation of the VPAC2 receptor in regions adjacent to the SCN through intraventricular infusion should affect activity levels. To test these hypotheses, we chronically infused a potent VPAC2 receptor agonist 44)] in the third ventricle of Syrian hamsters while monitoring wheel-running activity. In addition, we examined the effect of chronic application of BAY 55-9837 on period and amplitude of PER2 expression measured by bioluminescence in cultured SCN explants.