Multifactors Analysis On Hypnotic Activity Of Melatonin

Melatonin is an indolamine hormone mainly produced by the pineal gland. The well-described effects of melatonin include physiological sleep-promotion and sleep-wake cycle regulation. The dissertation mainly studied the influences of circadian rhythm system and GABAergic system on hypnotic activity of melatonin. In order to develop new melatonin compound, which has more effective and less side effect, melatonin was used together with some sleep-inducing agents in this paper.The results showed that melatonin had significant sedative and hypnotic activity by using methods of locomotor activity, potentiation of sodium pentobarbital-induced sleep in mice and electroencephalogram (EEG) analysis in rats. Melatonin prolonged the sleep time induced by sodium pentobarbital depending on the circadian stage with a peak at 8:00 and a trough at 16:00 when it administered orally to mice housed in 12h light/12h night cycle at six time intervals during the day. A similar result was obtained in rats by EEG recording. Hypnotic activity of melatonin displayed significantly during the day (experiment began at 8 a.m), but its effect became very weak during the night (experiment began at 8 p.m). It is indicated that hypnotic activity of melatonin has a time-dependent characteristic when the function of circadian rhythm is normal. Constant light and pinealectomy can destroy the function of circadian rhythm system. Melatonin markedly prolonged sleep time both in the mice exposed to constant light and in pinealectomized mice compared to that in normal mice. Melatonin also exhibited potent hypnotic effect when it was injected to rats exposed to constant light at 8 p.m. From above results, it is demonstrated that melatonin exhibits more significant hypnotic activity due to circadian rhythm system dysfunction.Prazosin hydrochloride, a specific antagonist of melatonin 3 (MT3) receptor, used together with melatonin, increased melatonin potentiation of sodium pentobarbital-induced sleep, but there was no interaction between melatonin and prazosin hydrochloride. It is indicated that hypnotic activity of melatonin may be not mediated by MT 3 receptor.Semicarbazide hydrochloride and L-malic acid, the blockers of synthetic enzyme forGAB A, had no influence on sleep when they were used alone. However, they blocked the hypnotic activity of melatonin. GABA, the endogenous agonist of GABA receptor, potentiated hypnotic activity of melatonin. The further study showed that flumazenil, the benzodiazepine antagonist, and picrotoxin, the ligand of picrotoxin site on GABAA receptor, significantly antagonized hypnotic activity of melatonin by using EEG analysis in rats. When bicuculline methiodide, a specific antagonist of GABA binding site on GABAA receptor, used together with melatonin, melatonin-induced increase in total sleep time (TS), slow wave sleep (SWS) and paradoxical sleep (PS), and decrease in wakeful time (W) were disappeared. However, there was an interaction only on PS between them. The influence of melatonin on GABA level in mice different brain areas was detected by using paper electrophoretic coupled dual wavelength thin layer scanning method and GABA release in rat hypothalamus was detected by using microdialysis coupled to high performance liquid chromatography with electrochemical detection. Melatonin significantly increased GABA level and release in hypothalamus. Hypothalamus is an important area for hypnotic activity of melatonin. These results indicate that melatonin exhibits its hypnotic activity through activating synthetic enzyme for GABA, increasing the level and release of GABA and hypnotic activity of melatonin may be mediate through benzodiazepine recognition site, picrotoxin site and partially through GABA binding site on GABAA receptor.This paper also studied hypnotic activity of melatonin used together with another endogenous sleep-inducing substances-oleamide. At low doses, hypnotic activity of melatonin used together with oleamide was better than they were used alone, however, there was no interaction bet...