S20098 Affects the Free-Running Rhythms of Body Temperature and Activity and Decreases Light-Induced Phase Delays of Circadian Rhythms of the Rat

Abstract

Mammalian endogenous circadian rhythms are entrained to the environmental day-night cycle by light exposure. Melatonin is involved in this entrainment by signaling the day-night information to the endogenous circadian pacemaker. Furthermore, melatonin is known to affect the circadian rhythm of body temperature directly. A striking property of the endogenous melatonin signal is its synthesis pattern, characterized by long-term elevated melatonin levels throughout the night. In the present study, the influence of prolonged treatment with the melatonin agonist S20098 during the activity phase of free-running rats was examined. This was achieved by giving S20098 in the food. The free-running body temperature and activity rhythms were studied. The present study shows that enhancement of the melatonin signal, using S20098, affected the free-running rhythm by gradual phase advances of the start of the activity phase, consequently causing an increase in length of the activity phase. A well-known feature of circadian rhythms is its time-dependent sensitivity for light. Light pulse exposure of an animal housed under continuous dark conditions can cause a phase shift of the circadian pacemaker. Therefore, in a second experiment, the influence of melatonin receptor stimulation on the sensitivity of the pacemaker to light was examined by giving the melatonin agonist S20098 in the food during 1 day prior to exposure to a 60-min light pulse of 0, 1.5, 15, or 150 lux given at circadian time (CT) 14. S20098 pretreatment caused a diminished light pulse-induced phase shift when a light pulse of low light intensity (1.5 lux) was given. S20098 treatment via the food was sufficient to exert chronobiotic activity, and S20098 treatment resulting in prolonged overstimulation of melatonin receptors is able to attenuate the effect of light on the circadian timing system.

Could agomelatine be the ideal antidepressant?

“…Drugs that influence the circadian apparatus are often referred as chronobiotics. The chronobiotic activity of agomelatine has been confirmed by many studies [55][56][57][58][59] and is due to an effect on the electrical activity of SCN neurons that is similar to that of melatonin, although more prolonged in duration [56]. Such a prolonged action of agomelatine is attributed to its tighter binding to MT 1 receptors [60].…”

Drug treatment of depression in the 2000s: an overview of achievements in the last 10 years and future possibilities

“…It is regulated via the cAMP signal transduction cascade (Foulkes et al 1997). A variety of animal studies and clinical trials in depressed patients suggest that agomelatine, a potent and specific synthetic melatonergic MT 1 and MT 2 receptor agonist (Zlotos 2005) with serotonin (5-HT) 2C receptor antagonistic properties (Millan et al 2003) within the central nervous system (CNS), has antidepressant effects (Tuma et al 2002). In addition similar like melatonin also agomelatine has been shown to exert antidopaminergic action involving striatal GABAergic mechanisms (Tenn et al 1997).…”

Recent Progress in Pharmacological and Non-Pharmacological Treatment Options of Major Depression

“…Animal studies suggest that agomelatine (S20098), a synthetic melatonin receptor agonist within the central nervous system (CNS), has activating and therefore antidepressant properties [32]. The putative antidepressant properties of agomelatine are subject of ongoing clinical trials.…”