MLT injected at the same clock time each day to rats free-running in DD entrains the circadian locomotor rhythm (49). Free running rhythms of lizards (68) and European starlings (25) entrain to daily injections but at a different phase to rats. In the nocturnal rat, entrainment takes place when the beginning of a coincides with injection time while in the diurnal starling and lizard it is the beginning of p that synchronizes to the injection. While daily infusions entrain both Siberian (Phodopus sungaris) and Syrian (Mesocricetus auratus) hamsters the phase angle can be peculiar (29) compared to rats, presumably demonstrating the differential effect of infUsion versus injection and not a species difference.
Since exogenous MLT entrains representatives from three classes of terrestrial vertebrates (lizards, birds and rodents) one would predict that the likelihood of it entraining humans and other primates would be high. However, a negative finding on primates (Sagerinus fuscicollis the saddleback tamarin) comes from an experiment conducted under an exotic LD regime (33). The LD cycle was steadily phase advanced by one hour per day and MLT administered at the same clock time each day failed to compete with the LD cycle.
In a temporal isolation study on humans in which the fractional desynchronisation procedure was used, MLT failed to strengthen the lengthening LD zeitgeber and prevent internal desynchronisation between the rhythm in the temperature and the sleep-wake cycle (71). Nevertheless, a synchronizing effect on the fatigue alertness rhythm was reported (71). However, from PRC to MLT in humans (34,36) it is evident that MLT was administered at entirely the wrong time to maintain entrainment.
There are several reports of successful entrainment of circadian rhythms of individual blind human subjects by MLT treatment. These include in single subjects, synchronization of a disturbed sleep-wake cycle (5 mg) (3), advancing sleep onset, stabilizing sleep and reducing day time naps (5 mg) (58) and entrainment (7.5 mg) (57). In the first subject (3), the free-running rhythms in both temperature and urinary cortisol were on further analysis found not to be entrained (22) whereas in the third subject (57) entrainment of the endogenous MLT rhythm was demonstrated, indicating true entrainment of the underlying circadian pacemaker. In a blind, retarded boy with Non-24-Hour Sleep Wake Disorder, MLT corrected sleep phase (43).
Thus the evidence to date in humans is ambiguous; synchronization of human sleep is reported, but in many subjects it is less likely that the clock is entrained, as plasma MLT rhythm may continue to free-run (6). The sleep-wake pattern of humans evidently is not equivalent to the rest-activity locomotor rhythm of rodents. However, since "feelings of well being" seem to depend on synchronizing sleep phase to nighttime (30), this may be all that is needed in clinical practice for an efficacious result.
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