Melatonin After Four Decades

Abstract

The field of melatonin research, like many of its participants, has reached a respectable “middle-age’’ after many growth phases, identity crises and maturational experiences. First identified by Aaron Lerner and his colleagues at Yale, melatonin (or N-acetyl-5-methoxytryptamine as the chemists would prefer) was originally of some interest because of its exquisitely potent effects on melanophore pigment dispersion. Subsequently, its biochemistry was elucidated and within the first decade the unex- pected and signature feature of its synthesis was discovered, viz its daily rhythmicity. Earlier clinical literature in which pubertal disorders were often associated with tumors of the pineal gland led researchers at about this time to the develop animal models for understanding melatonin’s involvement in reproductive processes. Despite occasional frustration and frequent controversy, what eventually emerged in the second decade was the recognition that melatonin does indeed participate in regulating reproductive activities in many, but apparently not all species, and that this function is critically time- dependent. Put another way, melatonin’s actions are often dissimilar when young versus old experimental animals are tested, but even more importantly, melatonin is only phys- iologically active when present in the organism’s bloodstream (from where it diffuses quickly throughout the body) at the appropriate time of day. It didn’t take long for this remarkable insight to permeate the field of chronobiology, out of which surprising new attributes for melatonin were found in the third decade. Even in the clinical field, mela- tonin was rapidly “transformed” into something more than a mere hormone. It thus became a key biological parameter for assessing circadian phase as well as a novel agent for modifying circadian clock function. Whereas for years the “secret” among well- travelled researchers was that melatonin could effectively mitigate the symptoms of jet lag, melatonin after its fourth decade is now being investigated in terms of innumer- able expressions of circadian rhythmicity from sleep-wake cycles and body tempera- ture rhythms to cerebral perfusion and cell proliferation. A truly major breakthrough for the field of melatonin research was the cloning of the first melatonin receptor by Steve Reppert’s laboratory some 5 years ago. Within only a few years many other species of melatonin receptor have been cloned, their tissue distribution mapped and signalling mechanisms identified. In this regard, the need for a logically consistent manner for assigning new receptors to the melatonin receptor subfamily led the IUPHAR earlier this year to recommend a new receptor nomenclature, which we have adopted in this book. It would be my personal plea to all current and future melatonin researchers that this classification be used, if for no other reason than to avoid the confusion similar to that which we all face with the variety of abbreviations currently used for melatonin (e.g., aMT, ML, MLT, MEL)!! The conference from which this book derives its inspiration was organized as a tribute to the person of Aaron Lerner. His unique contribution four decades ago to the field of basic and applied biology, i.e., the discovery of melatonin, is finally beginning to receive the intellectual scrutiny that it deserves, as could be seen in the excellent lec- tures and posters presented at this conference. In evolving scientifically from a hormone with actions on the skin to a chronobiotic and, possibly oncostatic molecule, melatonin research has engaged many physiologists, biochemists, pharmacologists, psychiatrists and endocrinologists. The majority of these still active individuals were in attendance at our melatonin conference in August and have benefited the present book with their diverse and informative chapters. While this current “assessment of its potential” is necessarily broad and multi-disciplinary, one can anticipate an even greater interface with other disciplines in the future as the full spectrum of melatonin’s biological actions become apparent. I would be negligent not to take this opportunity to thank a number of individ- uals who made the Hanseatic Endocrine Conference 1998 and ultimately this book pos- sible. For their untiring dedication to the many important organizational details I wish to thank A. Schade, P. Behring, P. Stegemann, Prof. R. Ivell, Dr. A. Mukhopadhyay, Prof. H. Schulte and Prof. F. Leidenberger, as well as the many members of the IHF whose time and support were tremendously helpful. Financial support from the Deutsche Forschungsgemeinschaft, GEFE e.V., Deutsche Gesellschaft fur Endokrinologie, IHF, Lundbeck A/S, Bristol Myers-Squibb, the SmithKline Beecham Foundation, Schering AG, Becton-Dickinson, Boehringer Mannheim, Buhlmann Laboratories AG, Genecraft, Sigma-Aldrich, Dianova GmbH, IBL GmbH, Stockgrand Ltd and Servier is also gratefully acknowledged.