94 Nocturnal MEL production is a direct output of the SCN circadian clock. Exogenous
MEL is effective at a time when endogenous MEL is not. produced or present in the general circulation. Consequently the effects of MEL administration in vivo, as important as they are in terms of Panobinostat potential clinical applications, appear not to be related to the role of endogenous MEL on circadian functioning. This conclusion is reinforced by the observation that to obtain entrainment of the circadian activity rhythm of rodents kept under constant, darkness, high doses of MEL have to be used, independently of the mode of administration.131,133,142 These doses of MEL Inhibitors,research,lifescience,medical produce peak serum levels 100- to 1000-fold higher than the endogenous MEL nighttime levels. The necessity of such a high dose of MEL is unlikely to be a consequence of its rapid metabolism. Appropriate photoperiodic response Inhibitors,research,lifescience,medical is, indeed, obtained when MEL is administered
via a similar subcutaneous infusion system with a dose that Inhibitors,research,lifescience,medical mimics the endogenous secretion profile.94,143 Most likely, this high dose of MEL is needed because it is an integral part of the response observed. Especially because in vitro administration of MEL can phase shift, the firing rate of SCN neurons in brain slices (rat, mouse),69,144 it is generally believed that. MEL mediates these effects through the high-affinity MET. receptors located within the SCN.29,107,125 This view is supported by the high correlation between the density of MEL receptors within the SCN and the ability of daily MEL administration to entrain
the free-running activity rhythm Inhibitors,research,lifescience,medical in mammals. Contrary to the rat, mouse, and Djungarian hamster, rodents that can be entrained by daily MEL administrations and in which a high density of MEL receptors is observed within the SCN, the mink (Muslela vison) does Inhibitors,research,lifescience,medical not. appear to have specific MEL receptors (at. least 2-iodomelatonin binding sites) within the SCN. This animal docs not entrain to MEL.89 Newborn Syrian hamsters express MET. receptors in the SCN, but shortly after birth the receptor number decreases.145,146 Young hamsters are entrainable by daily acute MET. administration, while in the adult. MET. cannot entrain129,147,148 or can only do so under particular Dipeptidyl peptidase experimental conditions (eg, long-term infusions).132,149 Since SCN-lesioned hamsters whose rhythmicity has been restored with fetal hypothalamic graft are entrained by daily MEL injection, and since MET. is known to accelerate the reentrainment of circadian rhythm in rat. subjected to a shift in the LD cycle,134 it is clear that the chronobiotic effect, of MEL is the consequence of a direct action on the clock.