CONTENTS
Introduction
Melatonin
Physiology and Pharmacology of Endogenous Melatonin
Exogenous Melatonin
Endogenous and Exogenous Melatonin and the Brain
Melatonin and Neurobehavior
Melatonin and Exploratory Behavior
Melatonin, Learning and Memory
Conclusion
References
ABSTRACT Melatonin, an indoleamine found in both plants and animals, is a pleiotropic signaling molecule. In animals, it plays an important role in the maintenance of the circadian rhythm and, to date, debates are still ongoing on its other functions and possible uses. Administered melatonin has effects on many behavioral processes, with animal models demonstrating its anticonvulsant, anxiolytic, antidepressant, and locomotor-suppressant and memory-modulating effects. Presently, melatonin research is looking at new horizons, where its role in the etiology and management of clinical conditions such as schizophrenia and dementia is being deeply examined. In this chapter, the sequence of melatonin metabolism and the relationship between melatonin, brain, and neurobehavior is discussed. The implications of exogenous administration of daytime melatonin and its effect on novelty-induced behaviors, learning, and memory are presented.
KEY WORDS: melatonin, brain, behavior, chronobiotic, endogenous, exogenous, learning, memory.
Introduction
Melatonin
Melatonin (N-acetyl-5-methoxytrypamine; Figure 23.1) is an indoleamine, first characterized and isolated from bovine pineal gland in 1958 by American dermatologist Aaron Lerner and his colleagues (Lerner et al., 1959; Arendt, 1988; Commai and Gobbi, 2014; Sugden et al., 2004), when it was noticed to be responsible for the lightening of frog skin through contraction of the epidermal melanophores. This is believed to be related to the mechanism by which some amphibians and reptiles change the color of their skin (Sugden et al., 2004), thus identifying the depigmenting factor that was first described in 1917 by McCord and Allen (Lerner, 1960).
Melatonin is found in humans, animals, bacteria, fungi, algae, and plants, including Tanacetum parthenium (feverfew), Hypericum perforatum (St John’s wort), rice, corn, tomato, grape, edible fruits, olive oil, wine, and beer (Tan et al., 2011; Lamont et al., 2011) Melatonin has been found in a number of tissues and organs that are able to biosynthesize the indoleamine and has been reported to secrete enzymes that catalyze the synthesis of melatonin. These tissues include astrocytes, glial cells, retinal cells, lymphocytes, bone marrow cells, mast cells and epithelial cells, organs like the gut, testes, ovary, placenta, and the skin. In 1939, a reference to the possible functional relationship between melatonin and carbohydrate metabolism was made by the Romanian Constantin Parhon in a short abstract (Parhon, 1939), and debates are still ongoing on melatonin and its possible uses and functions.
Endogenous melatonin is a highly pleiotropic signaling molecule secreted by the pineal gland, predominantly at night; it is primarily known as the signal of darkness (Arendt, 1998). Melatonin is secreted from the pineal gland in young and middle-aged individuals (Haimov et al., 1994; Peirpaoli and Regelson, 1995), and its secretion follows a circadian rhythm with high amplitude, while melatonin secretion from other sites follows a low-amplitude rhythm. In earlier reports, its secretion was believed to decrease with age; more recent studies, however, dispute this. Zeitzer et al. (1999) reported no significant difference in plasma melatonin concentrations in a group of 34 healthy elderly subjects aged between 65–81 years, and 98 healthy drug-free young men aged between 18–30 years. In the Zeitzer study, extensive screening led to the exclusion of subjects on melatonin-lowering drugs like beta blockers and nonsteroidal anti-inflammatory drugs, as well as subjects consuming alcohol, caffeine, or nicotine (Zeitzer et al., 1999). Extrapineal melatonin, however, is thought play a small role in the maintenance of the circadian rhythm, since studies have shown that pinealectomy diminishes this rhythm. It is speculated that melatonin from these sources is used, rather, in the defense against oxidative stress.
Physiology and Pharmacology of Endogenous Melatonin
Melatonin biosynthesis in humans and some other organisms involves four enzymatic steps from the essential dietary amino acid tryptophan. It is synthesized by the pinealocytes in a multistep process, beginning with hydroxylation of aromatic amino acid L-tryptophan to 5-hydroxytryptophan; this is catalyzed by tryptophan hydroxylase, an enzyme believed to be key in melatonin synthesis (Schallreuter, 1994). 5-Hydroxytryptophan is then converted to serotonin (5-hydroxytryptamine) by the aromatic amino acid decarboxylase, initially to hydroxytryptophan through hydroxytryptamine and eventually to melatonin. In the dark, aralkylamine N-acetyltransferase (AANAT), a key enzyme in melatonin biosynthesis, is activated, which catalyzes the conversion of serotonin to N-acetylserotonin, which is then converted to melatonin by the final enzyme, acetylserotonin O-methyltransferase (Lovenberg et al., 1967; Iuvone et al., 2005; Norman and Henry, 2012). Aralkylamine N-acetyltransferase is a key regulator of melatonin synthesis from tryptophan, as its gene AANAT is directly influenced by the photoperiod. Tryptophan hydroxylase (TPH), is another enzyme that is important in melatonin biosynthesis, albeit to a lesser extent than AANAT; it controls the availability of serotonin. The final step of melatonin synthesis is the conversion of N-acetylserotonin to melatonin by the enzyme serotonin N-acetyltransferase (SNAT), formerly known as hydroxyindole-O-methyl transferase (HIOMT) (Radomir et al., 2012). Endogenous melatonin upon synthesis by the pineal gland is secreted quickly into the blood and other bodily fluids, including cerebrospinal fluid (CSF) (Rousseau et al., 1999), saliva (Vakkuri et al., 1985), and bile (Tan et al., 1999). Levels of melatonin in the cerebrospinal fluid are usually higher than that seen in the blood. Approximately 50%–75% of melatonin found in the blood is bound reversibly to albumin and alpha-1-acid glycoprotein; it has a half-life estimated to be 30–60 min and first-pass metabolism in the liver results in a clearance rate of 90% (Pardridge and Mietus, 1980; Claustrat et al., 1986).
Melatonin metabolism occurs via three main pathways, which include: (1) the hepatic degradation pathway that produces 6-hydroxymelatonin (Radomir et al., 2012; Hardeland et al., 2011), (2) the indolic pathway that generates 5-methoxyindole acetic acid (5-MIAA) or 5-methoxytryptophol (5-MTOL) (Radomir et al., 2012), and (3) the kynuric pathway that produces N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) (Tan et al., 2007; Slominski et al., 2008). The most definitive physiological role melatonin is linked to is the regulation of the circadian (Quera and Hartley, 2012) and circannual or seasonal rhythms, and the conveyance of this information to body physiology for the organization of functions that vary with season.
In humans, however, functional relationships between endogenous melatonin rhythms and other physiologic processes remain uncertain. Melatonin also regulates physiologic functions such as reproduction, coat growth and color, appetite, body weight, and sleep (Jolanta et al., 2009; Arendt, 2000). Other functions modulated by melatonin include immune functions, contraction of smooth muscle, body temperature regulation, defense against oxidative stress, balancing of organismal energy metabolism, and retarding the aging process; it has also been described as a putative antihypertensive. Melatonin is a neurohormone with endocrine, paracrine, and autocrine activity (Chun-Qiu et al., 2011). It performs most of these functions by acting as a messenger of the suprachiasmatic nucleus (SCN).
Melatonin and its metabolites are potent antioxidants (Bavithra et al., 2013) that have both direct and indirect antioxidant activity. They act directly by aiding in the reduction of the body’s free radical burden and levels of both oxygen and nitrogen species. They are able to extend this antioxidant potential to all subcellular structures due to their highly lipophilic ability; melatonin has the advantage of being soluble in lipids and water, a unique character that enhances its cellular distribution, enabling its passage through the blood–brain barrier (Al-Omary, 2013). Melatonin’s indirect antioxidant activity resides in its ability to improve mitochondrial efficiency and stimulate the expression and activation of a number of antioxidants and potentiate their antioxidant activities. Many of melatonin’s actions are mediated through the interaction with specific membrane-bound receptors (Radomir et al., 2012; Slominski et al., 2008) such as MT1 and MT2, also known as Mel1a, and Mel1b, respectively (Dubocovich et al., 2010). Both these receptors are members of the G protein–coupled, seven-transmembrane receptor family (Dubocovich et al., 2003). Melatonin also acts through non-receptor-mediated mechanisms when it scavenges reactive nitrogen and oxygen species (Gomez-Moreno et al., 2010).
