Pituitary adenylate cyclase activating peptide phase shifts circadian rhythms in a manner similar to light

The endogenous circadian pacemaker in mammals is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Various cues can reset circadian rhythm phase, thereby entraining the internal rhythm to the environmental cycle, and these effects can be investigated using an in vitro method to measure phase shifts of the SCN. Although pituitary adenylate cyclase activating peptide (PACAP) is localized in retinal inputs to the SCN, it has been reported to alter clock phase only during the subjective day (Hannibal et al., 1997), whereas light alters phase only in the subjective night. In this study we show that PACAP can reset the clock in the photic pattern during the subjective night when applied in 10 pM to 1 nM doses. This appears to be mediated via a glutamatergic mechanism, possibly by potentiation of NMDA currents as is seen at 10-100 pM. Given at higher doses (>10 nM), PACAP shifts in the subjective day, apparently via activation of adenylate cyclase and increased intracellular cAMP. These results indicate dose and phase specificity of the effects of PACAP, and a new role as a transmitter in the retinohypothalamic tract.