The Discovery of Serotonin

THE DISCOVERY OF SEROTONIN MAURICE M. RAPPORT" Twenty years have passed since a paper with this title by Dr. Irvine Page appeared in this journal [I]. At that time the involvement of serotonin in a host ofphysiological functions was not understood, and the pharmacological properties were quite puzzling. Since then the discovery of 14 or more serotonin receptors has led to a frantic effort to develop new drugs to modify serotonin's actions, and this has generated renewed interest in the history of its discovery. What constitutes discovery is an interesting question, and one may distinguish several phases depending on the consequences of the new knowledge . There are three phases to the serotonin discovery: the first is detection ; the second, isolation and characterization as a pure substance; and the third, identification of the chemical structure as 5-hydroxytryptamine. Detection, the first phase, dating back to 1868, is well documented in several extensive reviews in the literature, indicating a broad interest in problems related to vasoconstriction [2, 3]. Isolation of the pure substance, the second phase, might have been very important if enough material could have been obtained to clarify problems that arose because of its presence. Identification, the third phase, proved to be critical, because it permitted the substance to be synthesized by organic chemists and thus to become available for study by scientists in many disciplines. This availability has now led to the elucidation of serotonin's participation in a large number of physiological processes. My work on this problem at the Cleveland Clinic began in February 1946, and there were two other principal participants, Dr. Arda A. Green and Dr. Irvine H. Page. I had completed the requirements for a Ph.D. in Organic Chemistry at CaI Tech in November 1945. Dr. Page had recently been appointed Research Director at the Cleveland Clinic. His major interests were *Department ofNeurology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. The author wishes to thank Dr. N. B. Reich and Dr. Sam Seiner for assistance in the preparation of this manuscript.© 1996 by The University of Chicago. All rights reserved. 0031-5982/97/4002-0987101.00 260 Maurice M. Rapport ¦ Discovery of Serotonin in cardiovascular pathology, mainly in essential and malignant hypertension and the possibility that vasoactive substances were responsible for the increase in peripheral resistance characteristic of these disorders. In the search for such substances, the existence of the "serum vasoconstrictor" released by platelet breakdown was an annoying source ofinterference. Dr. Green was a well-established physical biochemist with an in-depth experience in protein fractionation. She was trying to isolate a protein extracted from bovine kidney that seemed to arrest the course ofmalignant hypertension . Her assay was the perfused isolated rabbit ear that responded to the protein extracts by vasodilation, and throughout the work on serotonin she was in charge of the rabbit ear assay. It was initially quite difficult to interrupt Dr. Green's work. She was only willing to test a fraction of mine at the end of the day, because the usual result of such a test was that the ear preparation would cease to respond. Arda would then say "the ear didn't like that," and no further testingwould be possible. This rather severely limited what I could do experimentally, since almost every manipulation of serum created a new artifact that the "ear did not like." Two other problems also needed to be solved. One involved quantification , a necessary feature for a systematic study. Two features of the rabbit ear response—namely, the duration and the intensity of the vasoconstriction —could not be matched by any of the available constrictor substances, such as epinephrine, tyramine, and histamine. I found that a sample of serum deproteinized with alcohol and evaporated to dryness produced a brownish gum that retained its activity when kept frozen. An arbitrary weight of this material was adopted as a standard and used for each day's tests. This procedure permitted us to control the variable responses ofindividual ear preparations. Since the response was not linear with dose, quantification had to be based on diluting a test sample until the response was identical to that of the standard. The...