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0031-6997/03/5502-325-395$7.00
Pharmacol Rev 55:325-395, 2003

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Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters

Valerie Simonneaux and Christophe Ribelayga

Laboratoire de Neurobiologie des Rythmes, Unité Mixte Recherche 7518, Centre National de la Recherche Scientifique/Université Louis Pasteur, Strasbourg, France

Abstract
I. Introduction
II. Role of Melatonin
    A. Regulation of Seasonal Rhythms
    B. Regulation of Circadian Rhythms
    C. Other Roles of Melatonin
        1. Autocrine/Paracrine Effects.
        2. Modulation of Neurotransmission
        3. Effects of Melatonin on the Immune System.
        4. Antioxidant/Antiaging Property of Melatonin.
    D. Sites and Mechanisms of Action of Melatonin
    E. Conclusion: Melatonin Is a Time-Giver Endocrine Messenger
III. Neural and Humoral Inputs to the Mammalian Pineal Gland
    A. Structure and Ultrastructure of the Pineal Gland
    B. Neural Inputs
        1. Retino-Hypothalamo-Pineal Pathway.
            a. The Retino-Hypothalamic Tract.
            b. The Hypothalamic Endogenous Circadian Oscillator.
            c. Suprachiasmatic Nucleus of the Hypothalamus Outputs to the Pineal Gland.
        2. Central Pathways.
        3. Parasympathetic Pathways.
        4. Pathways from Other Neural Structures
    C. Endocrine Inputs
    D. Paracrine Inputs
    E. Conclusion: The Pineal Gland Is a Junction of Various Neural Inputs
IV. Indoleamine Metabolism in the Mammalian Pineal Gland
    A. Indoleamine Metabolic Pathways
    B. Tryptophan Hydroxylase
    C. Aromatic Amino Acid Decarboxylase
    D. Monoamine Oxidase
    E. Alcohol and Aldehyde Dehydrogenases
    F. Arylalkylamine-N-Acetyltransferase
    G. Hydroxyindole-O-Methyltransferase
V. Noradrenergic Regulation of Melatonin Synthesis in the Mammalian Pineal Gland
    A. Noradrenergic Regulation of Melatonin Synthesis in the Rat Pineal Gland
        1. Adrenergic Receptors of the Pineal Gland
            a. Subtype {beta}1
            b. Subtype {alpha}1
            c. Subtype {alpha}2
        2. Second Messengers Induced by Noradrenergic Stimulation.
        3. The Third Messengers/Transcription Factors Induced by Noradrenergic Stimulation.
        4. Acute Effects of Noradrenergic Stimulation on the Melatonin Synthesis Pathway.
        5. Mechanisms Involved in the Termination of Nocturnal Melatonin Synthesis.
        6. Effect of Light Exposure at Night.
        7. Consequences of Long-Term Noradrenergic Stimulation of the Pineal Gland.
    B. Noradrenergic Regulation of Melatonin Synthesis in Other Mammalian Species
        1. Daily Regulation of Melatonin Synthesis
            a. Daily Regulation of Melatonin Synthesis in Other Rodents.
            b. Daily Regulation of Melatonin Synthesis in Nonrodents.
            c. Conclusions.
        2. Seasonal Variations in Melatonin Synthesis
            a. Variations in the Duration of the Nocturnal Melatonin Peak.
            b. Variations in the Amplitude of the Nocturnal Melatonin Peak.
            c. Conclusions.
    C. Conclusion: Both AA-NAT and HIOMT Shape the Daily and Seasonal Profiles in Melatonin Synthesis
VI. Regulation of Melatonin synthesis in the Mammalian Pineal Gland by Other Transmitters
    A. Peptidergic Regulation of Melatonin Synthesis
        1. Vasoactive Intestinal Peptide, Pituitary Adenylate Cyclase Activating Peptide, and Histidine Isoleucine Peptide.
        2. Neuropeptide Y.
        3. Vasopressin and Oxytocin.
        4. Somatostatin.
        5. Substance P.
        6. Calcitonin Gene-Related Peptide.
        7. Secretoneurin.
        8. Hypocretin.
        9. Delta-Sleep Inducing Peptide.
        10. Natriuretic Peptides.
        11. Angiotensin.
        12. Opiate Peptides.
        13. Luteinizing Hormone-Releasing Hormone.
        14. Peptides to Come.
        15. Conclusion: (Neuro)Peptides Are True Pineal Transmitters.
    B. Other Nonadrenergic, Nonpeptidergic Transmitters of the Pineal Gland
        1. Serotonin.
        2. Dopamine.
        3. Acetylcholine.
        4. Glutamate.
        5. GABA.
        6. Taurine.
        7. Histamine.
        8. Adenosine and ATP.
        9. Nitric Oxide.
        10. Gonadal Steroids.
VII. General Conclusions and Perspectives
Melatonin, the major hormone produced by the pineal gland, displays characteristic daily and seasonal patterns of secretion. These robust and predictable rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes in photoperiodic species. In mammals, the nighttime production of melatonin is mainly driven by the circadian clock, situated in the suprachiasmatic nucleus of the hypothalamus, which controls the release of norepinephrine from the dense pineal sympathetic afferents. The pivotal role of norepinephrine in the nocturnal stimulation of melatonin synthesis has been extensively dissected at the cellular and molecular levels. Besides the noradrenergic input, the presence of numerous other transmitters originating from various sources has been reported in the pineal gland. Many of these are neuropeptides and appear to contribute to the regulation of melatonin synthesis by modulating the effects of norepinephrine on pineal biochemistry. The aim of this review is firstly to update our knowledge of the cellular and molecular events underlying the noradrenergic control of melatonin synthesis; and secondly to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis. This information reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism. This also clarifies the role of these various inputs in the seasonal variation of melatonin synthesis and their subsequent physiological function.

Address correspondence to: Valérie Simonneaux, Laboratoire de Neurobiologie Rythmes, UMR 7518 CNRS/ULP, 12, rue de l'Université, 67000 Strasbourg, France. E-mail: simonneaux{at}neurochem.u-strasbg.fr




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