Melatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high-affinity G protein–coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin®) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents.
Melatonin is a neurohormone primarily synthesized by the pineal gland following a circadian rhythm with a high level during the night and a low level during the day. Alterations in the synthesis and secretion of melatonin have been reported in various mood disorders, including major depressive disorder. However, the role of endogenous melatonin in the pathophysiology of depressive disorder is unclear. Melatonin primarily acts through two G protein-coupled receptors, termed MT and MT . The present study investigated the effect of genetic deletion of the MT and/or MT receptors on tests associated with depression- and anxiety-like behaviors in C3H/HeN mice. Deletion of the MT and/or MT receptors caused a deficit in hedonic and social interaction behavior, and increased anxiety-like behavior. It is likely that dysregulations of the MT and/or MT melatonin receptors could be involved in the pathophysiology of depression and anxiety.
The drug of abuse methamphetamine (METH) is known for its ability to enhance reward responses. The rewarding properties of psychostimulants have been shown to vary across time of day in mice. The goal of this study was to determine the role of the MT1 and MT2 melatonin receptors in METH-induced reward, as measured by the conditioned place preference (CPP) paradigm during the light and dark phases. C3H/HeN wild-type mice were trained for METH-induced CPP at either ZT 6–8 (ZT: Zeitgeber time; ZT 0 = lights on), when endogenous melatonin levels are low, or ZT 19–21, when melatonin levels are high. These time points also correspond to the high and low points for expression of the circadian gene Period1, respectively. The locomotor response to METH (1.2 mg/kg, ip) treatment was of similar magnitude at both times, however only C3H/HeN mice conditioned to METH at ZT 6–8 developed a place preference. C3H/HeN mice with a genetic deletion of either the MT1 (MT1KO) or MT2 (MT2KO) receptor tested at ZT 6–8 or ZT 19–21 did not develop a place preference for METH, though both showed a similar increase in locomotor activity following METH treatment when compared to wild-type mice. We conclude that in our mouse model METH-induced conditioned place preference is dependent on time of day and the presence of the MT1 or MT2 receptors, suggesting a role for melatonin in METH-induced reward.
Apart from the well known inhibitory effects of estradiol on food intake, meal size, and body weight in female rats that have been documented over the past thirty years, a more recent report presents the opposite finding; that a large dose of estradiol can increase food intake and weight gain in gonadally intact female rats presented with a palatable diet. The purpose of the present experiment was to further examine this hypothesis by evaluating the ability of estradiol to influence feeding behavior in ovariectomized rats presented with diets that differ in flavor and fat content. Female rats were given a cyclic regimen of estradiol benzoate treatment (5.0 or 20.0 µg) or the oil vehicle and were presented with the standard chow diet or a diet with a higher fat content and chocolate flavor. Food intake, meal size, and meal number were monitored three days after the first injection of estradiol or oil. Compared to the chow diet, food intake increased when animals had access to the chocolate/fat diet during the vehicle treatment condition. Both doses of estradiol significantly decreased food intake, meal size, and body weight gain when animals were presented with either the standard chow diet or the chocolate/fat diet. These findings indicate that estradiol does not stimulate the intake of a palatable diet in ovariectomized rats, and suggest that previous results showing that estradiol enhanced eating and weight gain stemmed from a disruption of the hypothalamic-pituitary-gonadal axis when intact females received a large dose of exogenous estradiol.
The hormone melatonin is synthesized from serotonin by two enzymatic reactions (AANAT and ASMT/HIOMT) in the pineal gland following a circadian rhythm with low levels during the day and high levels at night. The robust nightly peak of melatonin secretion is an output signal of the circadian clock to the whole organism.
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