Preface

Although serotonin (5-HT) was discovered as a neurotransmitter less than 80 years ago, the successive decades have yielded a dramatic increase in our knowledge of serotonin, its receptors, enzymes, transporters and accessory proteins and its associated functions. Serotonin constitutes one of the oldest neurotransmitter systems in nature; it is estimated to have originated about 800 million years ago. This enormous time span enabled the serotonergic complex to evolve into a highly important system involved in many important biological processes in the body, particularly in the central nervous, gastro-intestinal, cardiovascular and immune systems. It is remarkable that the neurotransmitter itself has not evolved during evolution, but the molecules with which it interacts have shown an amazing diversity, variability and extent and seem to vary according to species, organ, cell, gender and disease state. The complexity of the involvement of serotonin is illustrated in the chapters contributing to this volume.

In Chapter 1 investigators from various countries and backgrounds have collaborated on mathematical modeling of neurotransmitter metabolism, focusing on 5-HT and histamine, applying various techniques and trying to connect their findings to neuropsychiatric disorders, notably depression. By eloquently combining various advanced methods and techniques they present a new serotonin model of 5-HT synthesis, release, reuptake and autoreceptor control and make an intriguing connection to neuro-inflammation as a causative factor in major depression.

Chapter 2 deals with the interconnection between serotonin, sleep and depression. The involvement of 5-HT neurotransmission in sleep and wakefulness has been known since the sixties, but many questions have not been resolved. In this chapter a new hypothesis is formulated involving 5-HT and excessive long pre-morning periods of REM-sleep, leading to a complete stop of monoamine release. It is suggested that fragmentation of this sleep phase may have antidepressant effects.

Chapter 3 describes the putative role of the serotonergic system in post-traumatic stress disorder (PTSD), a troublesome condition that is increasing in prevalence worldwide. This review shows the involvement of the serotonergic system in the regulation of sensitivity to highly stressful events and how to cope with them.

Chapter 4 deals with the use of small molecule drugs for the treatment of Alzheimer's Disease which is developed on the basis of a mechanistic understanding of the Serotonin Receptors 4 and 6.

Chapter 5 deals with serotonergic brain mechanisms of aggression and sexual behavior, focusing on 5-HT1A- and 5-HT1B-receptors, as there is evidence for (partly) overlapping in CNS circuitry for aggression and sexual behavior. As 5-HT1B-receptors seem particularly involved in aggression and 5-HT1A-receptors in sexual behavior, their precise interrelationship is not clear and far from understood. This information is badly needed to develop anti-aggressive (serenic) and prosexual drugs for human applications.

Chapter 6 describes new ligands for 5-HT4- and 5-HT6-receptors that might create new treatments in the modulation of cognition and amyloid pathology. The chapter nicely describes recent progress in understanding how to modulate underlying systems by medicinal chemistry methods of advanced pharmacophores. This will hopefully lead to new pharmacological approaches and drugs to treat Alzheimer's disease.

Chapter 7 discusses the role of serotonin in cerebral edema after traumatic brain injury. Traumatic brain injury leads to very complex processes where many different mechanisms play a role. Serotonin is clearly involved in early cytotoxic edema after traumatic brain injury. Maintaining low serotonin levels in the brain immediately after an injury has neuroprotective effects and may contribute to a better outcome for the patient.

Chapter 8 is a nice overview of the role of 5-HT pathways in neuro-immuno communication and their role in autoimmune and inflammatory pathology in CNS diseases, including multiple sclerosis, Alzheimer's disease and mood disorders. The chapter also outlines the important role of the 'brain-gut axis' and shows the involvement of brain-gut communication in the pathogenesis and pathophysiology of several brain disorders.

This book excellently illustrates the broadness of research and therapy in the serotonergic field. It also indicates that new developments continuously occur in a 'seemingly old' system. It is evident that we still are only at the beginning of understanding the role of serotonin in health and disease.

> **Dr. Berend Olivier** Professor, Professor Emeritus Pharmacology of the Central Nervous System, Faculty of Sciences, Department of Psychopharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands

> > Adjunct Professor, Department of Psychiatry, Yale University School of Medicine, New Haven, USA

## **Chapter 1**
