A CONCEPT FOR A ROLE OF SEROTONIN AND NOREPINEPHRINE AS CHEMICAL MEDIATORS IN THE BRAIN

It is not the purpose of this paper to make a survey of the work suggesting that serotonin is a central neurohumoral agent, since much of this is being discussed by other contributors to this monograph. Rather, we should like to offer a concept that implicates serotinon and norepinephrine as chemical mediators of mutally antagonistic centers in the brain. This thesis, which is admittedly oversimplified, endeavors to explain the actions of the tranquilizing agents reserpine and chlorpromazine and the hallucinogenic agents LSD and mescaline in terms of interactions with serotonin and norepinephrine in the central nervous system. As presented here this concept may begin to trace the outlines of a coherent picture, but one, we are sure, that will bear only a faint resemblance to the picture that will ultimately emerge. The concept is only a working hypothesis, but i t has already proved useful in linking a number of unrelated observations and in suggesting certain experiments that might test it. It is fascinating to learn how the discovery of serotonin, a substance that appears to have no part in the general metabolism of cells, has proved to be of such significance to the pharmacologist, the biochemist, the neurophysiologist and, possibly, to the psychiatrist. When the vasoconstrictive material in blood platelets was finally isolated and identified as 5-hydroxytryptaminel1, i t was soon proved identical with the enteramine that Erspamer3 had extracted years before from the gastrointestinal tracts of the vertebrates and from other organs in the invertebrates. A number of notions concerning its role in the body were considered, most of which took into account its profound contractive action on smooth muscle. Among these possibilities were the control of vascular tone and, therefore, of systemic blood pressure; control of gastrointestinal motility; regulation of water excretion by affecting kidney arterioles; and regulation of hemostatic action by affecting blood vessels after release from platel e t ~ . ~ . Several of these suggestions can be more or less summarily dealt with a t once. Since serotonin is normally present in the body almost entirely in a bound and therefore presumably inactive form, i t is doubtful that there is enough of the free form circulating in plasma to affect the vascular tone either of the body as a whole or of the kidneys in particular. Results from our laboratory indicate that it is not involved in any obvious way in hemostasis, since animals and humans whose platelets have been depleted of serotonin by the administration of reserpine show no change in bleeding or clotting time.6 It is possible that serotonin controls some aspects of gastrointestinal motility, although no direct evidence is as yet forthcoming in this connection. The clue pointing to a role for serotonin in the functioning of the central