The adult suprachiasmatic nucleus (SCN) expresses a polysialylated form of neural cell adhesion molecule (PSA-NCAM) that modulates cell interactions. Previous studies have shown that PSA is important for photic entrainment of the SCN circadian clock, suggesting that changes in cell-cell interactions may contribute to the phase-resetting capacity of this system. A possible role for PSA in nonphotic circadian phase resetting was evaluated using the enzyme endoneuraminidase (endo N) to selectively remove PSA from the SCN. Pretreatment of rat brain slices containing the SCN with endo N enhanced the daytime phase-advancing effects of the serotonin agonist, 8-hydroxy-2-dipropylaminotetralin [8-OH-DPAT] (41% greater than inactivated enzyme controls; P<.05). Similarly, removal of PSA from the Syrian hamster SCN in vivo potentiated the daytime phase-advancing effects of behavioral arousal (sleep deprivation) and of systemic application of 8-OH-DPAT (61% and 220% greater, respectively, than inactivated enzyme controls; both P<.05). While endo N perturbation of both photic and nonphotic phase resetting suggests that PSA plays a central role in clock regulation, it is striking that the effects on the two inputs are opposite in direction. This difference could reflect the antagonistic relationship between photic and nonphotic signaling pathways. It could also be explained by a permissive role of PSA common to both inputs, which in and of itself would not specify direction of response. Such a bidirectional control mechanism, based on PSA's attenuation of cell-cell interactions, is well documented in the developing nervous system, and may be retained in plastic regions of the adult brain.