Neuropeptide Y-containing fibers project from the intergeniculate leaflet of the lateral geniculate nucleus to the suprachiasmatic nucleus. Previous studies have indicated that this pathway may be involved in non-photic resetting of the circadian clock. Therefore, we investigated the possibility that neuropeptide Y mediates phase shifts induced by a particular non-photic stimulus, a pulse of running in a novel wheel. Confining hamsters to a small nest box failed to block phase shifts induced by neuropeptide Y given at zeitgeber time 4; this indicates that increased locomotor activity is not necessary for the observed shifts. Antiserum raised against neuropeptide Y or normal serum was administered at circadian time 5 through a cannula aimed at the suprachiasmatic nucleus. The hamsters were then removed from their cages and placed in a novel wheel for 3 h. Hamsters that received normal serum and ran > 5000 revolutions in the novel wheel advanced their rhythms (mean shift 2.55 h +/- 0.22 S.E.M.) by amounts similar to those of unoperated hamsters. Administration of neuropeptide Y antiserum attenuated the shift normally associated with running in a novel wheel (mean shift 0.21 h +/- 0.14 S.E.M.). These studies indicate that the neuropeptide Y input from the lateral geniculate nucleus to the biological clock is involved in the phase shifts seen in response to novelty-induced wheel running. It also provides another example of the ability of antisera to alter behavior. This may be a useful approach in manipulations of neurochemical activity when antagonists are not yet available or poorly defined.