Serotonin and Behavior

Jack Barchas

• Publisher: Academic Press
• Year: 2012
• ISBN:
  9780323143660
• Topic: Medicine
• Subtopic: Pharmacology

Serotonin and Behavior contains the proceedings of the 1972 symposium on the behavioral effects of changes in brain serotonin, held at Stanford University in California. The papers explore the role of serotonin in behavior as well as the key biochemical and pharmacological issues involved in behavioral studies of severe psychiatric disorders in both humans and animals. The book is organized into eight sections comprised of 65 chapters, with topics ranging from the fundamental biochemistry and pharmacology of the enzymes synthesizing serotonin, particularly, tryptophan hydroxylase and its inhibitors, to the physiology and pharmacology of serotonin. Some papers discuss the link between the telencephalic content of serotonin and pain sensitivity. Other papers focus on the effects of altering serotonin on neurons in the central nervous system. There are chapters that explain the effects of altering serotonin on animal behavior, the relationship between serotonin and sleep, the use of high doses of probenecid to estimate central serotonin turnover in affective disorders and addicts, the behavioral and metabolic effects of L-tryptophan in unipolar depressed patients taking methadone, and amygdala unit activity as a reflection of functional changes in brain serotonergic neurons. Biochemists, pharmacologists, psychiatrists, psychologists, and anyone interested in psychopharmacology will find this book extremely useful.

Session 1

Biochemistry and Pharmacology: Tryptophan Hydroxylase and Inhibitors of Tryptophan Hydroxylase

INTRODUCTION TO BIOCHEMISTRY AND PHARMACOLOGY: TRYPTOPHAN HYDROXYLASE AND INHIBITORS OF TRYPTOPHAN HYDROXYLASE

Moderator. M.A. Lipton

Introduction

This promises to be a very comprehensive symposium with topic areas ranging from the fundamental biochemistry of the enzymes synthesizing serotonin through the effects of spontaneous and experimental alterations in serotonin level upon many aspects of behavior in man and animals. The program is organized in an ascending order of complexity and perhaps a descending order of precision. It might appear from this that investigators working in this area have systematically moved from chemistry and anatomy to psychology and clinical research. But, we all know that this is far from the case. Research on serotonin has moved forward very rapidly on many fronts simultaneously. The initial problem choices of investigators are determined by their training, talent and curiosity. Clinical research has often preceded basic research and interesting clinical hypotheses as often stimulate basic investigators as the other way around.

Nonetheless, with retrospective wisdom, it is appropriate to organize a symposium as this one has been. The first session begins with a series of seven papers dealing with fundamental biochemistry, physiology and pharmacology. The speakers will discuss the biochemistry of serotonin formation, our current knowledge of the mechanisms involved in the regulation of tissue serotonin concentrations, and the chemical nature of serotonin inhibitors and our knowledge of their mode of action.

DOES THE TOTAL TURNOVER OF BRAIN 5-HT REFLECT THE FUNCTIONAL ACTIVITY OF 5-HT IN BRAIN?

D.G. Grahame-Smith

Publisher Summary

This chapter discusses whether the total turnover of brain 5-hydroxytryptamine (5-HT) reflects the functional activity of 5-HT in brain. Many studies have been conducted in which the turnover of brain 5-HT has been determined based on the overall steady state system where synthesis of 5-HT equals its metabolism to 5-hydroxyindoleacetic acid (5-HIAA). Concentration of tryptophan in the brain is the most important factor determining the rate of brain 5-HT synthesis, because the rate-limiting enzyme tryptophan hydroxylase is not saturated with its substrate tryptophan. The small and large changes in the concentration of brain tryptophan alter the rate of synthesis of 5-HT. If tryptophan alone is given to rats, the brain 5-HT concentration rises only slightly, but the brain 5-HT turnover markedly increases, the evidence being the rise in brain 5-HIAA production.

Many studies have been done in which the turnover of brain 5-HT has been determined on the basis of the overall steady state system where synthesis of 5-HT equals its metabolism to 5-HIAA, as shown below.

Implicit for the relevance of these studies to the behavioural role of 5-HT is the assumption that the 5-HIAA, which is produced, reflects the amount of 5-HT being used in functional activity within the brain. This must be the thought in the minds of most people, because there would be little point in studying the effect of alterations in behaviour upon the turnover of 5-HT, or the levels of 5-HIAA in the CSF of patients with mental disease, unless it was thought that there was some relationship between total turnover and the functional activity of 5-HT in brain.

Now if indeed the steady state situation was such that every molecule of 5-HT that was synthesized in brain was metabolized to 5-HIAA after having been functionally active, moment to moment synthesis of 5-HT would be crucially important in determining the functional level of 5-HT within the neuron. The situation would then hold that if synthesis were not turned off at an appropriate moment, than pushing a molecule of 5-HT in would cause one to spill over into functional activity. Even on biological first principles this is unlikely. Some experiments I have recently reported (Grahame-Smith, 1971) imply this is not the case.

It is apparent that the concentration of tryptophan in the brain is the most important factor determining the rate of brain 5-HT synthesis, because the rate-limiting enzyme tryptophan hydroxylase is not normally saturated with its substrate tryptophan. I (Grahame-Smith, 1971) and Fernstrom and Wurtman (1971a) have shown that both small and large changes in the concentration of brain tryptophan alter the rate of synthesis of 5-HT.

If tryptophan alone is given to rats it can be shown that the brain 5-HT concentration rises only slightly, but that the brain 5-HT turnover more markedly increases, the evidence being the rise in brain 5-HIAA production. However, with tryptophan loading alone no obvious behavioural change occurs in rats.

Contrast this situation with that which occurs if tryptophan is given to rats pretreated with a monoamine oxidase inhibitor. After pretreatment with a monoamine oxidase inhibitor, small doses of tryptophan (5 mg/kg) cause the animals to become extremely hyperactive and hyperpyrexial in a stereotyped manner, the degree of this excitation correlating with the rate of accumulation of 5-HT in the brain. The evidence is now very good that it is the accumulation of brain 5-HT or a derivative of it which causes the excitation.

These two situations differ only in regard to the inhibition of monoamine oxidase. In the first, 5-HT is being synthesized then metabolized to 5-HIAA without any obvious behavioural change and in the second, 5-HT is being synthesized at an equivalent rate, accumulating because of MAO inhibition, exceeding the binding mechanisms, and spilling over into functional activity. How is it that in the absence of MAO inhibition, the production of 5-HIAA is not associated with evidence of serotonergic functional activity if indeed all the 5-HIAA which is produced derives from a functionally active 5-HT? That is difficult to explain, and it seems more likely that when no MAO inhibitor is given, 5-HT is formed during tryptophan loading, but is metabolized intraneuronally without ever becoming functionally active. Because very small increases in brain tryptophan which minimally increase the rate of brain 5-HT, nevertheless cause hyperactivity and hyperpyrexia when MAO is inhibited, it is possible that normally 5-HT is synthesized in excess of functional requirements. If this is so, newly synthesized 5-HT probably passes into one of two compartments, either into a storage compartment or when that is full or adequate, into a compartment in which it is accessible to monoamine oxidase when it is metabolized intraneuronally. The controlled activity of monoamine oxidase, the ability of 5-HT to get to that enzyme, the control of the storage compartment, would all combine to finely control the level of a functional pool of 5-HT within the neurons. I find it very difficult to conceive that the regulation of a crucial functional pool of neuronal 5-HT can depend upon the fine regulation of tryptophan hydroxylation when this enzymatic activity is so depend...

Table of contents

• Cover image
• Title page
• Table of Contents
• Inside Front Cover
• Copyright
• Inside Front Cover
• CONTRIBUTORS
• PRECLINICAL PSYCHOPHARMACOLOGY RESEARCH REVIEW COMMITTEE (JANUARY 1972)
• PREFACE
• WELCOMING STATEMENT
• Session 1: Biochemistry and Pharmacology: Tryptophan Hydroxylase and Inhibitors of Tryptophan Hydroxylase
• Session 2: Physiology and Pharmacology: Localization, Uptake, and Metabolism of Serotonin
• Session 3: Physiology and Pharmacology: Depletion of Serotonin
• Session 4: Neurophysiology: Effects of Altering Serotonin on Central Nervous System Neurons
• Session 5: Animal Behavioral Studies: Behavioral Effects of Altering Serotonin in Animals
• Session 6: Animal Behavioral Studies — Sleep: The Relation of Serotonin to Sleep
• Session 7: Human Behavior: Tests for Serotonin Utilization in Humans and Effects of Precursor Loading in Various Disorders
• Session 8: Human Behavior: Tests for Serotonin Utilization in Humans and Effects of Precursor Loading in Various Disorders
• REFERENCES
• ABBREVIATIONS
• SUBJECT INDEX