In vivo pharmacological effects of
ramelteon (TAK-375), a novel, highly MT1/MT2-selective receptor agonist, were studied in rats to determine
ramelteon's ability to reentrain the circadian rhythm after an abrupt phase advance. Experiments were also conducted to assess the potential cognitive side effects of
ramelteon and its potential to become a
drug of abuse. After an abrupt 8-h phase shift,
ramelteon (0.1 and 1 mg/kg, p.o.) and
melatonin (10 mg/kg, p.o.) accelerated reentrainment of running wheel activity rhythm to the new lightdark cycle.
Ramelteon (3-30 mg/kg, p.o.) and
melatonin (10-100 mg/kg, p.o.) did not affect learning or memory in rats tested by the water maze task and the delayed match to position task, although
diazepam and
triazolam impaired both of the tasks. Neither
ramelteon (3-30 mg/kg, p.o.) nor
melatonin (10-100 mg/kg, p.o.) demonstrated a rewarding property in the conditioned place-preference test, implying that MT1/
MT2 receptor agonists have no abuse potential. In contrast,
benzodiazepines and
morphine showed rewarding properties in this test. The authors' results suggest that
ramelteon may be useful for treatment of
circadian rhythm sleep disorders without adverse effects typically associated with
benzodiazepine use, such as learning and memory impairment, and
drug dependence.