Abstract
Melatonin exerts its actions through membrane MT1/MT2 melatonin receptors, which belong to the super family of G-protein-coupled receptors consisting of the typical seven transmembrane domains. MT1 and MT2 receptors are expressed in various tissues of the body either as single ones or together. A growing literature suggests that the melatonergic system may be involved in the pathophysiology of mood and anxiety disorders. In fact, some core symptoms of depression show disturbance of the circadian rhythm in their clinical expression, such as diurnal mood and other symptomatic variation, or are closely linked to circadian system functioning, such as sleep-wake cycle alterations. In addition, alterations have been described in the circadian rhythms of several biological markers in depressed patients. Therefore, there is interest in developing antidepressants that have a chronobiotic effect (i.e., treatment of circadian rhythm disorders). As melatonin produces chronobiotic effects, efforts have been aimed at developing agomelatine, an antidepressant with melatonin agonist activity. The present paper reviews the role of the melatonergic system in the pathophysiology of mood and anxiety disorders and the clinical characteristics of agomelatine. Implications of agomelatine in “real world” clinical practice will be also discussed.
Highlights
Melatonin exerts its actions through membrane MT1/MT2 melatonin receptors, which belong to the super family of G-protein-coupled receptors consisting of the typical seven transmembrane domains
This study showed that agomelatine displays some characteristics of antidepressant drug action in the transgenic mouse model, effects that could be partially related to its chronobiotic properties [85]
In the first study where agomelatine was reported to be effective in the treatment of anhedonia, Di Giannantonio et al found a significant improvement in the Snaith Hamilton Rating Scale (SHAPS) [138]
Summary
The neurohormone melatonin (N-acetyl-5-methoxytryptamine) is prominently, albeit not exclusively, synthesized in the pineal gland and is secreted in a phasic manner, since its circulating levels vary in a daily cycle. Despite an increase in mRNA expression during the daytime, surface expression of the melatonergic receptor in SCN neurons has been reported to be very low during the day and high at night, paralleling melatonin’s trough and peak [17] These findings suggest that the levels of circulating melatonin elicit a feedback regulation on the surface receptor amount, causing a downregulation of receptors with blood peaks. Regulation of melatonin receptor expression is under multiple other biological factors, e.g., estradiol levels, which cooperate to modulate melatonergic signaling in its different steps. Melatonergic inhibition of SCN activity is blunted by melatonin itself through the regulation of surface receptor expression [26] by their desensitization. It has been demonstrated that the melatonin MT1 receptor is mostly involved in the control of REM sleep [40]
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