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Neurobiology, Pathophysiology, and Treatment of Melatonin Deficiency and Dysfunction

By Rüdiger Hardeland

Abstract

Melatonin is a highly pleiotropic signaling molecule, which is released as a hormone of the pineal gland predominantly during night. Melatonin secretion decreases during aging. Reduced melatonin levels are also observed in various diseases, such as types of dementia, some mood disorders, severe pain, cancer, and diabetes type 2. Melatonin dysfunction is frequently related to deviations in amplitudes, phasing, and coupling of circadian rhythms. Gene polymorphisms of melatonin receptors and circadian oscillator proteins bear risks for several of the diseases mentioned. A common symptom of insufficient melatonin signaling is sleep disturbances. It is necessary to distinguish between symptoms that are curable by short melatonergic actions and others that require extended actions during night. Melatonin immediate release is already effective, at moderate doses, for reducing difficulties of falling asleep or improving symptoms associated with poorly coupled circadian rhythms, including seasonal affective and bipolar disorders. For purposes of a replacement therapy based on longer-lasting melatonergic actions, melatonin prolonged release and synthetic agonists have been developed. Therapies with melatonin or synthetic melatonergic drugs have to consider that these agents do not only act on the SCN, but also on numerous organs and cells in which melatonin receptors are also expressed

Topics: Review Article
Publisher: The Scientific World Journal
OAI identifier: oai:pubmedcentral.nih.gov:3354573
Provided by: PubMed Central
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    1. A .C a r r i l l o - V i c o ,J .M .G u e r r e r o ,P .J .L a r d o n e ,a n dR .J . Reiter, “A review of the multiple actions of melatonin on the immunesystem,”Endocrine,vol.27,no.2,pp.189–200,2005.
    2. (2004). A .C a r r i l l o - V i c o ,J .R .C a l v o ,P .A b r e ue ta l . ,“ E v i d e n c eo f melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine, and/or paracrine substance,”
    3. (2011). A benefit-risk assessment of agomelatine in the treatment of major depression,”
    4. (1976). A functional analysis of circadian pacemakers in nocturnal rodents. IV. Entrainment: pacemaker as clock,”
    5. (2010). A genomewide association study of citalopram response in major depressive disorder,”
    6. (1987). A model for the study of the acute effects of melatonin in man,”
    7. (2006). a n dP .Z e e ,“ E ffects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia,”
    8. (1999). A new concept for melatonin deficit: on pineal calcification and melatonin excretion,”
    9. (1998). A significant correlation between melatonin deficiency and endometrial cancer,”
    10. (2001). A study of light/dark rhythm of melatonin in relation to cortisol and prolactin secretion in schizophrenia,”
    11. (2008). A three pulse phase response curve to three milligrams of melatonin in12
    12. (1986). Abnormal circadian rhythm of melatonin in diabetic autonomic neuropathy,”
    13. (2007). Acquisition of oxidative DNA damage during senescence: the first step toward carcinogenesis?”
    14. (2007). Actions of melatonin, its structural and functional analogs in the central nervous system and the significance of metabolism,”
    15. (2003). Acu˜ n a - C a s t r o v i e j o ,G .E s c a m e s
    16. (2011). Aging, immunity,
    17. (2009). Agomelatine: new drug: adverse effects and no proven efficacy,”PrescrireInternational,vol.18,no.104,pp.241–245,
    18. (2006). An efficacy, safety, and dose-response study of Ramelteon in
    19. (2011). Analgesic effects of melatonin: a review of currentThe Scientific World Journal 15 evidence from experimental and clinical studies,”
    20. (2009). andD.X.Tan,“Melatonin:anestablishedantioxidantworthy of use in clinical trials,”
    21. (2004). Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin18 The Scientific World Journal receptors,”
    22. (2005). Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance,”
    23. (2011). Association of polymorphism in the promoter of the melatonin receptor 1A gene with schizophrenia and with insomnia symptoms in schizophrenia patients,”
    24. (2007). Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice,”
    25. (1999). Augmentation of indices of oxidative damage
    26. (2009). Batteries not included: diagnosis and management of mitochondrial disease,”
    27. (2007). Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORβ knockout,”
    28. (2009). Bidirectional communication between sleep and circadian rhythms and its implications for depression: lessons from agomelatine,”
    29. (2000). Case of a mentally retarded child with non-24 hour sleepwake syndrome caused by deficiency of melatonin secretion,”
    30. Cerebrovascular melatonin MT1-receptor alterations in patients with Alzheimer’s disease,”
    31. (2009). Chronic inflammation and oxidative stress as a major cause of agerelated diseases and cancer,”
    32. (2007). Circadian genes, rhythms and the biology
    33. (2010). Circadian integration of metabolism and energetics,”
    34. (2008). Circadian photoreception: ageing and the eye’s important role in systemic health,”
    35. (1992). Circadian rhythm abnormalities in totally blind people:incidenceandclinicalsignificance,”JournalofClinical Endocrinology and Metabolism,
    36. (2000). Circadian rhythm abnormalities of melatonin in Smith-Magenis syndrome,”
    37. (2006). Circadian rhythm disorder in a rare disease:
    38. (2007). Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm: an
    39. (2010). Clinical aspects of melatonin intervention
    40. Clinical uses of melatonin: evaluation of human trials,”
    41. (2007). Clock gene expression in the retina of melatonin-proficient (C3H) and melatonin-deficient (C57BL) mice,”
    42. (2011). Congenital diaphragmatic hernia in Smith-Magenis syndrome: a possible locus at chromosome 17p11.2,”
    43. (2008). control mechanisms, actions and bioactive metabolites,” Cellular and Molecular Life Sciences,
    44. (2010). Convergence of linkage, gene expression and association data demonstrates the influence of the RAR-related orphan receptor alpha (RORA) gene on neovascular AMD: a systems biology based approach,”
    45. (2006). Could agomelatine be the ideal antidepressant?”
    46. (2009). Critical appraisal and update on the clinical utility of agomelatine, a melatonergic agonist, for the treatment of major depressive disease
    47. (2002). D.M.Berson,F.A.Dunn,andM.Takao,“Phototransduction by retinal ganglion cells that set the circadian clock,”
    48. (1999). Daily melatonin administration at middleagesuppressesmaleratvisceralfat,plasmaleptin,and
    49. (2000). Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat,”
    50. (1996). Daily rhythm of serum melatonin in patients with dementia of the degenerate type,”
    51. (1999). Daily rhythm of serum melatonin levels and effect oflightexposureinpatientswithdementiaoftheAlzheimer’s type,”
    52. (1990). Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer’s disease,”
    53. (1999). Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer’s disease, and apolipoprotein
    54. (1993). Decreased nocturnal plasma melatonin levels in patients with recurrent acute intermittent porphyria attacks,”
    55. (2009). Defining chronodisruption,”
    56. (2006). Disorder of the saliva melatonin circadian rhythm in patients with Meniere’s disease,”
    57. (2008). Disorders of mitochondrial function,”
    58. (2006). Disposition kinetics and tolerance of escalating single doses of ramelteon, a highaffinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia,”
    59. (2010). Distinct contributions of rod, cone, and melanopsin photoreceptors to encoding irradiance,”
    60. (2007). Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer’s disease,”
    61. (2007). DNA damage, cellular senescence and organismal ageing: causal or correlative?”
    62. (2007). Drug Insight: the use of melatonergic agonists for the treatment of insomnia—focus on ramelteon,”
    63. (1998). e, “Disruption of retinoidrelated orphan receptor β changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice,”
    64. (2007). E.Sa vaskan,R.J ock ers,M.A y oubetal.,“TheMT 2 melatonin receptor subtype is present in human retina and decreases
    65. (1991). Effect of a 15 minute light pulse on nocturnal serum melatonin levels in human volunteers,”
    66. (2008). Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomizedcontrolledtrial,”JournaloftheAmericanMedical Association,
    67. (1992). Effect of tryptophan administration on circulating melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract,”
    68. (2002). Effects of pinealectomy on the levels and the circadian rhythm of plasma homocysteine in rats,” J o u r n a lo fP i n e a lR e s e a r c h ,
    69. (2009). Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia,”
    70. (2009). Endogenous melatonin provides an effective circadian message to both the suprachiasmatic nuclei and the pars tuberalis of the rat,”
    71. (2000). Entrainment of free-running circadian rhythms by melatonin in blind people,” The New England
    72. (2009). Evidence for genetic association of RORB with bipolar disorder,”
    73. (2000). Evidence that Alzheimer’s disease is a microvascular disorder: the role of constitutive nitric oxide,”
    74. (2010). G o o l e y ,S .M .W .R a j a r a t n a m ,G .C .B r a i n a r d
    75. (2002). Gastrointestinal melatonin: localization, function, and clinical relevance,”
    76. (2000). Gene regulation by melatonin,”
    77. (2010). Genetic variants in MTNR1B affecting insulin secretion,”
    78. (2010). Genome-wide association scan of trait depression,”
    79. (2011). Gr´ ozer et al., “Association study of BMP4, IL6, Leptin, MMP3, and MTNR1B gene promoter polymorphisms and adolescent idiopathic scoliosis,”
    80. (1976). Human circadian rhythms: a multioscillatory system,” Federation Proceedings,
    81. (2005). Hypothalamic regulation of sleep and circadian rhythms,”
    82. (2006). i s c h e r ,A .K a l s b e e ke ta l . ,“ P i n e a lc l o c k gene oscillation is disturbed in Alzheimer’s disease, due to functionaldisconnectionfromthe‘masterclock’,”TheFASEB
    83. (2000). i t e r a ,M .A .A r i a s ,J .A .M a l d o n a d o - C o c c oe ta l . ,“ T h e effect of melatonin in patients with fibromyalgia: a pilot study,”
    84. (2006). Immunocytochemical demonstration of day/night changes of clock gene protein levels in the murine adrenal gland: differences between melatonin-proficient (C3H) and melatonin-deficient (C57BL) mice,”
    85. (2007). Impact of melatonin receptors on pCREB and clock-gene protein levels in the murine retina,”
    86. (2006). Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice,”
    87. (1996). Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats,”
    88. (2002). Increased melatonin 1a-receptor immunoreactivity in the hippocampus of Alzheimer’s disease patients,”
    89. (2006). Increased REM sleep associated with melatonin deficiency after pinealectomy: a case study,”
    90. (2007). Inhibition of fatty acid transport and proliferative activity in tissueisolated human squamous cell cancer xenografts perfused in situ with melatonin or eicosapentaenoic or conjugated linoleic acids,”
    91. (2006). Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment,” Trends
    92. (2010). Investigational melatonin receptor agonists,”
    93. (2009). Key research opportunities in immune system aging,”
    94. (2008). L´ opez et al., “Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice,”
    95. (2000). La importancia del ritmo circadiano y de la melatonina para evitar el estr´ es oxidativo. Implicaciones en la investigaci´ on del trabajo a turnos rotatorio,”
    96. (2007). Light and darkness fail to regulate melatonin release in critically ill humans,”
    97. (2011). Long-term safety and efficacy of ramelteon in Japanese patients with chronic insomnia,”
    98. (1989). M c I n t y r e ,T .R .N o r m a n ,G .D .B u r r o w s ,a n dS
    99. (2009). M.Echizenya,S.Iwaki,H.Suda,andT.Shimizu,“Paradoxical reactionstohypnoticagentsinadolescentswithfree-running disorder,”PsychiatryandClinicalNeurosciences,vol.63,no.3,
    100. (2006). Maintenance of proteins and aging: the role of oxidized protein repair,”
    101. (2002). Mammalian melatonin receptors: molecular biology and signal transduction,”
    102. (2000). Melatonin administration can entrain the free-running circadian system of blind subjects,”
    103. (1991). Melatonin administration to blind people: phase advances and entrainment,”
    104. (2009). Melatonin ameliorates high fat diet-induced diabetes and stimulates glycogen synthesis via a PKCζ-Akt-GSK3β pathway in hepatic cells,”
    105. (2002). Melatonin and aging,”
    106. (2011). Melatonin and associated signaling pathways that control normal breast epithelium and breast cancer,”
    107. (1992). Melatonin and cortisol secretion in patients with primary obsessive-compulsive disorder,”
    108. (2000). Melatonin and epileptic seizures in patients with acute intermittent porphyria,”
    109. (2007). Melatonin and human chronobiology,” Cold Spring Harbor Symposia
    110. (2007). Melatonin and its influence on immune system,”
    111. (2009). Melatonin and melatonergic drugs on sleep: possible mechanisms of action,”
    112. (2005). Melatonin and nitric oxide: two required antagonists for mitochondrial homeostasis,”
    113. (2009). Melatonin and tryptophan circadian profiles in patients with advanced nonsmall cell lung cancer,”
    114. (2007). Melatonin and type 2 diabetes—a possible link?”
    115. (2002). Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy,” Current Topics in
    116. (2011). Melatonin as a natural ally against oxidative stress: a physicochemical examination,”
    117. (2008). Melatonin beyond its classical functions,”
    118. (2009). Melatonin deficiency and disrupted circadian rhythms in pediatric survivors of craniopharyngioma,”
    119. (1995). Melatonin effect on daytime sleep in men: suppression of EEG low frequency activity and enhancement of spindle frequency activity,”
    120. (2010). Melatonin effect on plasma adiponectin, leptin, insulin, glucose, triglycerides and cholesterol in normal and high fat-fed rats,”
    121. (1998). Melatonin improves cerebral circulation security margin in rats,”
    122. (1979). Melatonin in human cerebrospinal fluid in daytime: itsoriginandvariationwithage,”LifeSciences,vol.25,no.11,
    123. (2010). Melatonin in septic shock: some recent concepts,” J o u r n a lo fC r i t i c a lC a r e ,
    124. (2003). Melatonin increases oestradiol-induced bone formation in ovariectomized rats,”
    125. (1999). Melatonin inhibition of cancer growth in vivo involves suppression of tumor fatty acid metabolism via melatonin receptor-mediated signal transduction events,”
    126. (1998). Melatonin mediates two distinct responses in vascular smooth muscle,”
    127. (2009). Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production,”
    128. (2006). Melatonin receptor (MT1) knockout mice display depression-like behaviors and deficits in sensorimotor gating,”
    129. (2011). Melatonin receptor 1A gene polymorphism associated with polycystic ovarysyndrome,”GynecologicandObstetricInvestigation,vol.
    130. (2003). Melatonin reduces body weight gain in sprague dawley rats with diet-induced obesity,”
    131. (2001). Melatonin rhythm abnormalities and sleep disorders in the elderly,”
    132. (2003). Melatonin rhythmicity: effect of age and Alzheimer’s disease,”
    133. (1994). Melatonin rhythms in Arctic urban residents,”
    134. (2002). Melatonin secretion and increased daytime sleepiness in childhood craniopharyngioma patients,”
    135. (1999). Melatonin secretion rhythm disordersinpatientswithseniledementiaofAlzheimer’stype with disturbed sleep-waking,”
    136. (1992). Melatonin shifts human circadian rhythms according to a phase-response curve,”
    137. (1994). Melatonin synthesis in the gastrointestinal tract and the impact of nutritional factors on circulating melatonin,”
    138. (2006). Melatonin treatment in obese patients with childhood craniopharyngioma and increased daytime sleepiness,”
    139. (2002). Melatonin-immune system relationships,” Current Topics in
    140. (2006). Melatonin— nature’s most versatile biological signal?”
    141. (2003). Melatonin—a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin,”
    142. (2005). Melatonin, aging, and age-related diseases: perspectives for prevention, intervention,
    143. Melatonin, endocrine pancreas and diabetes,”
    144. (2009). Melatonin, mitochondrial electron flux and leakage: recent findings and resolution of contradictory results,”
    145. (2012). Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling,”
    146. (1993). Melatonin: a potent, endogenous hydroxyl radical scavenger,”
    147. (2009). Melatonin: signaling mechanisms of a pleiotropic agent,”
    148. (2008). Membrane phospholipids, lipoxidative damage and molecular integrity: a causal role in aging and longevity,”
    149. (2000). Migraine, as compared to other headaches, is worse daring midnight-sun summer than during polar night: a questionnaire study in an arctic population,”
    150. (2007). Minireview: entrainment of the suprachiasmatic clockwork in diurnal and nocturnal mammals,”
    151. (2006). Mitochondrial disease: powerhouse of disease,”
    152. (2009). Mitochondrial medicine: entering the era of treatment,”
    153. (2011). Molecular analysis of the Retinoic Acid Induced 1 gene (RAI1) in patients with suspected smith-magenis syndrome without the 17p11.2 deletion,”
    154. (2009). NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats,”
    155. (2006). Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback,”
    156. (2009). Neuroprotection by radical avoidance: search for suitable agents,”
    157. (2009). New approaches in the management of insomnia: weighing the advantages of prolonged-release melatonin and synthetic melatoninergic agonists,” Neuropsychiatric Disease and Treatment,
    158. (2010). New vistas on oxidative damage and aging,”
    159. (2007). Night shift work and the risk of endometrial cancer,”
    160. (2006). Nocturnal melatonin concentration is correlated with illness severity in patients with septic disease,”
    161. (1989). Nocturnal plasma melatonin levels in migraine: a preliminary report,”
    162. (1997). Nocturnal plasma melatonin profile and melatonin kinetics during infusion in status migrainosus,”
    163. (1992). o n t e l e o n e ,M .M a j ,M .F u s c o ,D .K e m a l i ,a n dR .J .R e i t e r , “Depressed nocturnal plasma melatonin levels in drug-free paranoid schizophrenics,”
    164. (1994). Oxidative damage andmitochondrialdecayinaging,”Proceedingsofthe National Academy of
    165. (2008). Parkinson’s disease as a neuroendocrine disorder of circadian function: dopamine-melatonin imbalance and the visual system in the genesis and progression of the degenerative process,”
    166. (2006). Pineal and cortical melatonin receptors MT1 and MT2 are decreased in Alzheimer’s disease,”
    167. (2011). pleiotropic, orchestrating regulator molecule,”
    168. (2010). Polymorphism in the PER3 promoter associates with diurnal preference and delayed sleep phase disorder,”
    169. (2005). Positive relationship between melatonin receptor type 1B polymorphism and rheumatoid factor in rheumatoid arthritis patients in the Korean population,”
    170. (2007). Possible therapeuticvalueofmelatonininmildcognitiveimpairment: a retrospective study,”
    171. (1995). Precocious puberty and decreased melatonin secretion due to a hypothalamic hamartoma,”
    172. (2010). Prospective study of common variants in the retinoic acid receptor-related orphan receptor α gene and risk of neovascular age-related macular degeneration,”
    173. (2011). Publication bias and outcome reporting bias: agomelatine as a case example,”
    174. (2001). R e i t e r ,D .A c u ˜ n a - C a s t r o v i e j o ,D .X .T a n ,a n dS . Burkhardt,“Freeradical-mediatedmoleculardamage:mechanisms for the protective actions of melatonin in the central nervous system,”
    175. (2003). R e i t e r ,D .X .T a n ,J .C .M a y o ,R .M .S a i n z ,J .L e o n ,a n dZ . Czarnocki, “Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans,”
    176. (1986). r o a d w a ya n dJ .A r e n d t ,“ D e l a y e dr e c o v e r yo fs l e e pa n d melatoninrhythmsafternightshiftworkinAntarcticwinter,”
    177. (2010). Ramelteon attenuates age-associated hypertension and weight gain in spontaneously hypertensive rats,”
    178. (2005). Reduced hippocampal MT2 melatonin receptor expression in Alzheimer’s disease,”
    179. (2004). Regulation of antioxidant enzymes: a significant role for melatonin,”
    180. (2005). Relative coordination to unknown “weak zeitgebers” in free-running blind individuals,”
    181. (2010). Removal of melatonin receptor type 1 induces insulin resistance in the mouse,”
    182. (2010). Restactivity cycle and melatonin rhythm in blind free-runners have similar periods,”
    183. (2005). Reviews,
    184. (2005). Role of melatonin in neurodegenerative diseases,”
    185. (2008). Role of melatonin receptors in the effects of melatonin on BDNF and neuroprotection in mouse cerebellar neurons,”
    186. (2006). S´ anchez-Barcel´ o, “Smith-Magenis syndrome: a case report of improved sleep after treatment with β1-adrenergic antagonists and melatonin,”
    187. (2009). S.R.Pandi-Perumal,I.Trakht,V.Srinivasanetal.,“Theeffect of melatonergic and non-melatonergic antidepressants on sleep: weighing the alternatives,”
    188. (2009). Safety and subjective sleep effects of ramelteon administration in adults and older adults with chronic primary insomnia: a 1-year, open-label study,”
    189. (2007). Seasonal affective disorder: a clinical update,”
    190. (1999). Seasonal changes of human circadian rhythms in
    191. (2007). Seasonal variation in serum concentrations of reproductive hormones and urinary excretion of 6-sulfatoxymelatonin in men living north and south of the Arctic Circle: a longitudinal study,”
    192. (1997). Self-reported sleep disturbance as a prodromal symptom in recurrent depression,”
    193. (2004). Serum melatonin and urinary 6-sulfatoxymelatonin in major depression,”
    194. (2010). Sleep and rhythm consequences of a genetically induced loss of serotonin,”
    195. (1994). Sleep disorders and melatonin rhythms in elderly people,”
    196. (2003). Sleep spindles: an overview,”
    197. (1992). Some perturbations that disturb the circadian melatonin rhythm,”
    198. (1999). Stress, aging, and brain oxidative damage,”
    199. (1987). Suppression of nocturnal plasma melatonin and 6-sulphatoxymelatonin by bright and dim light
    200. (2005). T.Hayakawa,M.Uchiyama,Y.Kameietal.,“Clinicalanalyses of sighted patients with non-24-hour sleep-wake syndrome: a study of 57 consecutively diagnosed cases,”
    201. (2009). Tasimelteon, a melatonin agonist for the treatmentofinsomniaandcircadianrhythmsleepdisorders,” Current Opinion
    202. (2008). The association of nocturnal serum melatonin levels with major depression in patients with acute multiple sclerosis,”
    203. (2005). The basic physiology and pathophysiology of melatonin,”
    204. (2010). The brain’s aging immune system,”
    205. (2010). The chronobiology, etiology and pathophysiology of obesity,”
    206. (1993). The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates,”
    207. (2007). The dark side of light at night: physiological, epidemiological, and ecological consequences,”
    208. (2009). The melatonin receptor MT1 is required for the differential regulatory actions of melatonin on neuronal “clock“ gene expression in striatal neurons in vitro,”
    209. (2003). The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways,”
    210. (1999). The oncostatic action of melatonin in an ovarian carcinoma cell line,”
    211. (2007). The phase shift hypothesis for the circadian component of winter depression,”
    212. (2007). The role of circadian clock genes in mental disorders,”
    213. (2009). The role of the thalamus in sleep, pineal melatonin production, and circadian rhythm sleep disorders,”
    214. (1999). The use of melatonin for the treatment of insomnia,”BiologicalSignalsandReceptors,v ol.8,no .1-2,pp .
    215. (2009). Timing light treatment for eastward and westward travel preparation,”
    216. (1998). Tissue retention and subcellular distribution of continuously infused melatonin in rats under near physiological conditions,”JournalofPinealResearch,vol.25,no.4,pp.251– 259,
    217. (2009). Trakht et al., “Pathophysiology of depression: role of sleep and the melatonergic system,”
    218. (2010). Urinary 6-sulphatoxymelatonin levels and risk of breast cancer in premenopausal women:
    219. (2006). V.Srinivasan,M.Smits,W.Spenceetal.,“Melatonininmood disorders,”WorldJournalofBiologicalPsychiatry,v ol.7,no .3,
    220. (2000). Variability of interactions between neuroendocrine immunological functions physiological aging and dementia of the Alzheimer’s type,”
    221. (2011). Verster et al., “Pharmacotherapy of insomnia with ramelteon: safety, efficacy and clinical applications,”

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