Melatonin is N-acetyl-5-methoxytryptamine (Figure 16–2), a simple methoxylated and N-acetylated product of serotonin found in the pineal gland. It is produced and released primarily at night and has long been suspected of playing a role in diurnal cycles of animals and the sleep-wake behavior of humans. Melatonin receptors have been characterized in the central nervous system and several peripheral tissues. In the brain, MT1 and MT2 receptors are found in membranes of neurons in the supra-chiasmatic nucleus of the hypothalamus, an area associated— from lesioning experiments—with circadian rhythm. MT1 and MT2 are seven-transmembrane Gi protein-coupled receptors. The result of receptor binding is inhibition of adenylyl cyclase. A third receptor, MT3, is an enzyme; binding to this site has a poorly defined physiologic role, possibly related to intraocular pressure. Activation of the MT1 receptor results in sleepiness, whereas the MT2 receptor may be related to the light-dark synchronization of the biologic circadian clock. Melatonin has also been implicated in energy metabolism and obesity, and administration of the agent reduces body weight in certain animal models. However, its role in these processes is poorly understood, and there is no evidence that melatonin itself is of any value in obesity in humans. Other studies suggest that melatonin has antiapoptotic effects in experimental models. Recent research implicates melatonin receptors in depressive disorders. Insomnia associated with autism spectrum disorder may respond to melatonin. Melatonin is promoted commercially as a sleep aid by the food supplement industry (see Chapter 64). There is an extensive literature supporting its use in ameliorating jet lag. It is used in oral doses of 0.5–5 mg, usually administered at the destination bedtime. Ramelteon is a selective MT1 and MT2 agonist that is approved for the medical treatment of insom-nia. This drug has no addiction liability (it is not a controlled substance), and it appears to be distinctly more efficacious than melatonin (but less efficacious than benzodiazepines) as a hypnotic. It is metabolized by P450 enzymes and should not be used in individuals taking CYP1A2 inhibitors. It has a half-life of 1–3 hours and an active metabolite with a half-life of up to 5 hours. Ramelteon may increase prolactin levels. Tasimelteon is a newer MT1 and MT2 agonist that is approved for non-24-hour sleep-wake disorder. Agomelatine, an MT1 and MT2 agonist and a 5-HT2C antagonist, is approved in Europe for use in major depressive disorder.
by chemical triggers such as cancer chemotherapy drugs. 5-HT1P and 5-HT4 receptors also play important roles in enteric nervous system function.
Like histamine, serotonin is a potent stimulant of pain and itch sensory nerve endings and is responsible for some of the symptoms caused by insect and plant stings. In addition, serotonin is a powerful activator of chemosensitive endings located in the coronary vascular bed. Activation of 5-HT3 receptors on these afferent vagal nerve endings is associated with the chemoreceptor reflex (also known as the Bezold-Jarisch reflex). The reflex response consists of marked bradycardia and hypotension, and its physiologic role is uncertain. The bradycardia is mediated by vagal outflow to the heart and can be blocked by atropine. The hypotension is a consequence of the decrease in cardiac output that results from bradycardia. A variety of other agents can activate the chemoreceptor reflex. These include nicotinic cholinoceptor agonists and some cardiac glycosides, eg, ouabain.