However, all animals responded in such a way that, once entrained, their active phase occurred in the shorter time interval between the MEL signals. This finding suggests that to achieve entrainment, MEL has to induce either a phase delay (when the period was shortened) or a phase advance (when the period was lengthened). Such a dual effect of MEL
has also been reported in other studies. For example, when rats experience a 5-h phase advance of the dark onset in LD conditions, those injected daily at the new dark onset reentrained Inhibitors,research,lifescience,medical with a decreased latency, some of the animals did so by phase delays, whereas others did so by phase advances.134 Infusion of MEL has been reported to entrain hamsters or Arvicanihis ansorgei, a diurnal rodent, by Inhibitors,research,lifescience,medical inducing phase advances when the free-running period was longer than 24 h and phase delays when the period was shorter than 24 h.132,135 All these observations strongly suggest that, the effects of exogenous MEL depend on the period before entrainment. Does melatonin cause “true” entrainment? Entrainment means that the period of the observed rhythm must adjust to and equal the Zeitgeber cycle (T), and a stable phase relationship must be established between the rhythm and Zeitgeber cycle.136 According to the nonparametric
model of entrainment, this synchronization process occurs through daily phase shifts, with the size and direction Inhibitors,research,lifescience,medical of shifts defined in the phase-response curve (PRC).137 This has been demonstrated by experiments
using light, as a synchronizer and little is known about the synchronizer properties of MEL and, for example, the limits of entrainment to MEL are not. yet well defined. In a Inhibitors,research,lifescience,medical recent study, Slotten ct al138 have studied this problem by administering MEL for a series of T values. The results indicate that the limiting phase-advance value, to which the rat activity rhythm entrains to MEL infusion, is approximately 35 min. Inhibitors,research,lifescience,medical Entrainment occurred at about circadian time (CT) 12; thus, at this phase of the activity cycle, MEL infusion induced the phase advance necessary to entrain the rhythm. The maximal daily phase-shift values defined by the MEL PRC139 and the magnitude of phase-shift responses to a http://www.selleckchem.com/products/carfilzomib-pr-171.html single MEL injection140 ranges from 15 to 52 min. The entrainment limits found in this study correspond quite well to these maximal phase-advance values. We can thus conclude that in the rat, daily acute MEL administration Casein kinase 1 causes “true” entrainment as defined by Enright.141 Until now, such experiments have never been replicated with a MEL agonist. Sites of action for the chronobiotic effects of melatonin In all the experiments reported above, the responsiveness to MEL is restricted to a narrow window of sensitivity, which is generally late in the subjective afternoon, but. depends upon the duration of the MEL signal as well as the previous free-running period. The finding that pinealectomized rats entrain to daily MEL administration133,140 indicates that endogenous MEL is not.
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