The melatonergic system: effects on sleep and implications for the treatment of psychiatric disorders

Abstract

The circadian pacemaker or biological clock, located in the hypothalamic suprachiasmatic nucleus, is the generation site of circadian rhythms. The light/dark cycle is the circadian pacemaker's dominant synchronizing agent, though it is also influenced by neurotransmitters and the phase-shifting effects of various chemical and pharmacological components, of which melatonin (N-acetyl-5-methoxytryptamine) is the most well established. In recent years, melatonin and melatonin analogs have been commercialized in many countries, mainly with hypnotic purposes. A new compound, agomelatine, has been recently synthesized and studied. Among melatonin analogs, this drug possesses unique pharmacological and clinical features; it is an antagonist at 5-HT2B and 5-HT2C receptors and has well established antidepressant and anxiolytic properties. Agomelatine opens new perspectives in the chronobiotic treatment of depression. The purpose of the present review was to elucidate the effects of the melatonergic system on sleep and the implications for the treatment of psychiatric disorders. Introduction: circadian and sleep-wake systemsMany biological functions are regulated by biological rhythms, among which circadian rhythms (Latin: circa, about; dies, day) are the most extensively studied and the best understood. They determine daily rhythmicity in behavior, core body temperature, sleep, feeding, drinking, and hormonal levels. 1,2 These circadian rhythms prepare the organism to anticipate daily changes in the environment and are not simply driven by the 24-hour environmental cycle, since they persist in the absence of time cues. 3 The circadian pacemaker, or biological clock, is the generation site of circadian rhythms. In mammals, the biological clock is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus, above the optic chiasma. It is noteworthy that most SCN efferent projections remain within the limits of the hypothalamus, and the best studied projection of SCN outside the hypothalamus is a multisynaptic projection to the pineal gland (see later). 4 SCN neurons isolated and kept in culture for several days still continue to show approximately 24-hour rhythms in action potential frequency. Metabolically, the SCNs show peak activity during the subjective day. This increased level of metabolism is paralleled by the increased electrophysiological activity evident from brain slice recordings. 5 The mean circadian period generated by the human SCN is approximately 18-24 hours. To remain perfectly entrained to the 24-hour cyclicity of the environment, ChronoPhysiology and Therapy downloaded from https: //www.dovepress.com/ by 44.224.250.200 on 11-Jul-2020 For personal use only.

Is There a Role for Agomelatine in the Treatment of Anxiety Disorders? A Review of Published Data

“…Unlike agomelatine, the anxiolytic effects were seen independently of the time of day of its administration (12). Since the pre-treatment with a selective melatonergic antagonist prevented the anxiolytic effect of agomelatine in the evening, but not in the morning, the anxiolytic effect may be related to the 5-HT2c antagonistic property of such a drug (13).…”

“…The combined actions of agomelatine on MIl/MT2 and 5-HT2c receptors facilitate the resynchronization of altered circadian rhythms and abnormal sleep patterns. Agolomelatine appears effective in treating various mood disorders (12,13).…”

Agomelatine beyond Borders: Current Evidences of Its Efficacy in Disorders Other than Major Depression

“…It has been suggested that the anxiolytic effect may be related to the 5-HT2c antagonistic property of such a drug [ 47 ]. In fact, it has been demonstrated that mice genetically lacking 5-HT2c receptors showed reduced anxiety, whereas in other experimental models, 5-HT2c receptor agonists show anxiogenic properties [ 48 ]. The antagonism of 5-HT2c receptors induced by agomelatine especially in the amygdala and hippocampus may be associated with anxiolytic properties [ 49 ] and, always through the blockade of 5-HT2c receptors, agomelatine may also enhance extracellular levels of noradrenaline (NA) in hippocampus, therefore increasing anxiolytic response [ 50 ].…”

Approaches to therapy for depressions in neurology: prospects for the use of agomelatine

“…Кроме того, длительное повышение уровня норадреналина в лобных долях способствует развитию противоболевого эффекта, механизм которого аналогичен таковому СИОЗСиН, но без воздействия на обратный захват нейротрансмиттеров [44] 5 . Существуют экспериментальные данные об анксиолитическом эффекте блокады 5-HT2C-рецепторов: у мышей с генетическим дефектом этого типа рецепторов отмечался патологически низкий уровень тревоги, а некоторые агонисты оказывали протревожное действие [45].…”