On a Proposed Theory for the Mechanism of Action of Serotonin in Brain

Abstract

Because it was difficult to explain the diverse effects of centrally acting drugs on the basis of the single neurohumoral agent acetylcholine (ACh), Brodie and Shore [1, 2] proposed in an interesting hypothesis that 5-hydroxytryptamine (serotonin or 5-HT) and norepinephrine might act as the main neurohumors of the trophotropic and ergotropic systems in brain. Much of the recent data from Brodie’s laboratories have been explained in terms of this theory [3–6]. The theory was based on the concepts of Hess [7, 8], namely, that there is a functional integration of the autonomic nervous system with the rest of the brain and that a subcortical system exists which consists of separate and antagonistic divisions, the ergotrophic and trophotropic. These ideas completely omit from discussion any reference to the ACh-cholinesterase (ChE) system. Data in the literature suggest that ACh is an important link in the chain of biochemical events associated with excitation of brain neurons, and in the author’s opinion ACh should be included in any theory of neurohumoral action [9–11]. Furthermore, the criteria necessary for a neurohumoral classification as used for serotonin and norepinephrine—such as (1) stored in an inactive form, (2) easily changed to a free or active form, (3) localized in different parts of the brain at varying concentration levels, (4) an enzyme present for its synthesis, and (5) an enzyme present for its destruction—apply equally well for ACh. In addition, when one compares the activities of cholinesterase and monoamine oxidase (MAO), the enzymes which keep ACh and 5-HT at physiological levels, it is interesting that in the brain the ratio is approximately 100 in favor of ChE activity, whereas in the peripheral organs, such as the liver, it is a small fraction of this value [12, 13]. Even if one suggests that ChE is normally present in great excess, a comparison of ACh content with 5-HT in the brain of some species from which data is available indicates that the former is present in amounts about ten times higher [see ref. 14, 15 for comparison in the rat, ref. 16 for rabbit midbrain]. Such data, taken together with the other facts, suggested to the author that ACh rather than 5-HT could be the more important neurohumoral agent in brain. If a trophotropic division exists in brain, then ACh could take the role suggested originally for 5-HT. One would then be left to explain the role of serotonin.