The Serotonin System

History, Neuropharmacology, and Pathology

Mark Tricklebank, Eileen Daly

• Publisher: Academic Press
• Year: 2019
• ISBN:
  9780128133248
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

The Serotonin System: History, Neuropharmacology, and Pathology provides an up-to-date accounting on the physiology and pathophysiology of serotonin and the role it plays in behavioral functions. In addition, the book explores the potential roles of 5-HT1 in neurodevelopmental disorders and summarizes the history of the discovery and development of serotonergic drugs for the treatment of neuropsychiatric disorders. This concise, yet thorough, volume is the perfect introduction to this critical neurotransmitter. It is ideal for students and researchers new to the study of behavior, neuropsychiatry or neuropharmacology, but is also a great resource for established investigators who want a greater perspective on serotonin.

• Examines the role of serotonin in physiological functions and neuropsychiatric disorders
• Provides in-depth knowledge on all aspects of the serotonin system
• Explores serotonergic receptors as targets for both current and new therapeutic compounds

Chapter One

The metabolism of indoleamines

Mark D. Tricklebank and Daniel Martins, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom

Abstract

The indoleamine serotonin is involved in many different functions of the central nervous system. There is however no longer a need to precede its hypothesized role as a neurotransmitter agent—with the word “putative” we think that role is totally accepted. The synthesis of 5-HT is now well defined, but less clear is its definitive role in neuropsychiatric disorders. Early work focused on levels of this amine in blood and urine, an approach that although viable and convenient is limited in the inferences they allow regarding the levels of serotonin release in the brain. A recent study using fast-cyclic voltammetry in the human brain while subjects performed a complex stock market game strongly suggests we have missed a key aspect of the phasic release of the transmitter and its potential role in controlling decision making. Where we have previously been searching for metabolic changes of large effect size and perhaps prolonged duration across the life span, pulses of release of millisecond duration may be much more important. The opportunity to widely approach this question is currently out of scope methodologically though. The work of Martin Sarter’s lab working with acetylcholine voltammetry has strongly indicated that this might be the case for cholinergic transmission as well, where phasic release seems to play key roles in monitoring the detection of stimulus cues. Clearly in vivo voltammetry in human brain is always going to be a rare opportunity and until somebody defines new noninvasive means of investigating serotonin release over a millisecond timeframe, decisions on the exact role of serotonin in controlling behavior are always going to be subject to questions of temporal specificity. Despite this limitation, our knowledge of serotonin metabolism is now both broad and specific. There is no doubt that compounds inhibiting 5-HT reuptake after its release has benefited millions of people suffering from depression since their introduction in the 1950s. Many specific points of metabolic control from both the melatonin and kynurenine metabolic branches of tryptophan metabolism have yet to be investigated as potential drug targets, notwithstanding the possibilities provided by the existence of multiple serotonin receptor subtypes (see Serotonin receptors nomenclature).

Keywords

Serotonin (5-HT); metabolism; phasic release; neuropsychiatric disorders

Introduction

The history of the discovery of serotonin is described in a detailed and quite excellent way by Patricia Whitaker Azmitia [1–4] in an article published in Neuropsychopharmacology in 1999. Recognizing that cardiovascular disease was the overriding cause of premature death in the 1930s and 1940s, biological and pharmaceutical research was heavily concentrated on the discovery of the causes of hypertension and heart disease. The serotonin story begins with the Italian Vittorio Erspamer who focused his life’s work on the isolation of drugs from natural sources. He particularly concentrated on nitrogenous substances causing the contraction of smooth muscle that can be found in the skin and intestines of a variety of small animals. In the process, he found one substance in the enterochromaffin cells of mammalian gut which he called enteramine [5]. Its potential functional importance was amplified to him when he discovered the same compound in the salivary glands of the octopus. In 1952, enteramine was established as the same muscle contractant that Twarog and Page [6] had identified in clotted blood and that they called serotonin (tonic substance in serum, hence serotonin). Serotonin was later identified chemically as 5-hydroxytryptamine by Rapport, Green, and Page [6]. Serotonin was then found by Betty Twarog to be present in both rodent and human brains. However, the detailed architecture of its cell bodies and projection fields had to wait for Falk and Hillarp to develop their fluorescence histochemical technique in order to probe and demonstrate its extensive distribution in brain tissue [7]. It was immediately seen to be concentrated very selectively within the large multipolar neurons of the midline raphe cells first noticed by Ramon and Cajal [8]. Once its chemical structure was determined as 5-hydroxytryptamine (Fig. 1.1), a major role in psychosis was hypothesized. This hypothesis stemmed from the fact that serotonin’s actions on smooth muscle in the periphery could be antagonized by the powerful psychotomimetic agent accidentally discovered by the medicinal chemist Albert Hofmann [9] while working on alkaline extracts of the ergot fungus growing on rye [10] to identify circulatory and respiratory stimulants. The compound was structurally related to serotonin and later identified to be lysergic acid diethylamide (LSD). This work led Brodie and Shore [11] proposed that serotonin and norepinephrine might act as opposing neurochemical systems analogous to adrenaline and noradrenaline in the sympathetic and parasympathetic systems, respectively. Nevertheless, it was not until 1943 that Hofmann took the step to experiment with his own compound and surely was blissfully unaware of the massive impact that his experiment, accidental or purposeful, would have on the world. After falling from his bicycle, Hofmann sank into a not unpleasant intoxicated state and perceived an uninterrupted stream of fantastic images with intense kaleidoscopic colors. Hofmann had discovered a psychoactive substance of extraordinary potency whose threshold dose turned out to be only 20 μg. As Hofmann’s images gradually subsided, they gave way to anxiety and the belief that his neighbor was a malevolent witch. Many similar folk stories of paranoia have endured: the story of the man who convinced that he had become an orange and who was immobilized by the fear of being plunged into a liquidizer to make juice. The electrophysiologist George Aghajanian [12] was the first to lower microelectrodes into the midline of the rodent brain to discover that the cells there displayed a slow and regular discharge pattern that was immediately blocked by iontophoretic administration of serotonin. LSD was given the name Delysid and sold by Sandoz in 1947 for clinical applications in psychiatry—first as a means of modeling psychosis. Sidney Cohen, a psychoanalyst who worked with Aldous Huxley together, thought that LSD would have a beneficial facilitating effect in psychotherapy allowing people to access their deep unconscious thoughts and feelings, curing alcoholism, and enhancing creativity. LSD as an investigative and potential therapeutic agent’s cause was championed by Timothy Leary, an American psychologist who very successfully tapped into the post-war youth culture of discontent with authority and wanted to explore the beneficial effects of LSD on psychiatric patients in controlled settings. For the emerging generation of biological psychiatrists wanting to throw off the shackles and unscientific principles of Freudian psychiatry and engage with the exciting developments in biology and medicine, LSD demonstrated with beautiful imagery the fact that consciousness had a biochemical basis. If a few micrograms of a compound could induce such profound alterations of perception and belief, surely all mental illness could ultimately be explained by altered brain biochemistry. Such revolutionary thoughts captured the culture of the times and LSD rapidly became the recreational drug of choice, giving freedom to experience the hitherto inaccessible unconscious spaces and so allow spiritual enlightenment, giving the individual the strength and courage to fight post-war authoritarianism, violence, repression, and injustice. Governments were uncharacteristically quick to spot what they considered to be an immoral use of a substance and both the United States and the United Kingdom declared possession and use of LSD prohibited in 1966 in the United States and 1970 in the United Kingdom. This did not happen without first taking the opportunity to test for themselves its potential use as a military weapon. Indeed, in 2006, the British Guardian newspaper reported that MI6 paid out thousands of pounds in compensation to servicemen who were fed LSD without their consent in clandestine experiments designed to demonstrate the drug’s ability to control the mind for military advantage. They thought it could act as a truth drug and force any captured enemy forces to confess the crimes of their leaders. The experiments were unsuccessful but brought on by fear that communist states had such substances. MI6 was not alone. In 1975, United States President Gerald Ford personally apologized to the family of a CIA operative who...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• List of Contributors
• Editors’ Biography
• Preface
• Chapter One. The metabolism of indoleamines
• Chapter Two. Neurodevelopmental roles and the serotonin hypothesis of autism spectrum disorder
• Chapter Three. The role of serotonin receptors in the control of cardiovascular function
• Chapter Four. Serotonin receptors nomenclature
• Chapter Five. A perspective: from the serotonin hypothesis to cognitive neuropsychological approaches
• Chapter Six. Endocrine and genetic moderation of serotonin systems and the psychopathology of affective disorders
• Chapter Seven. Serotonin and sexual behavior
• Chapter Eight. Serotonin and cognitive flexibility
• Chapter Nine. Serotonin and aggression
• Chapter Ten. Serotonin and sleep
• Chapter Eleven. Serotonin and the psychedelics
• Chapter Twelve. Serotonin and nociception: from nociceptive transduction at the periphery to pain modulation from the brain
• Chapter Thirteen. Serotonin and feeding regulation
• Chapter Fourteen. The outlook for the development of serotonergic drugs as therapeutic medications for psychiatric disorders
• Index