PII S0361-9230(01)00614-1 Modern views on an ancient chemical: Serotonin effects on cell proliferation, maturation, and apoptosis Efrain C. Azmitia 1,2 * Departments of 1 Biology and 2 Psychiatry, Center for Neural Science, New York University, New York, NY, USA ABSTRACT: Evolutionarily, serotonin existed in plants even be- fore the appearance of animals. Indeed, serotonin may be tied to the evolution of life itself, particularly through the role of tryptophan, its precursor molecule. Tryptophan is an indole- based, essential amino acid which is unique in its light-absorb- ing properties. In plants, tryptophan-based compounds capture light energy for use in metabolism of glucose and the genera- tion of oxygen and reduced cofactors. Tryptophan, oxygen, and reduced cofactors combine to form serotonin. Serotonin-like molecules direct the growth of light-capturing structures to- wards the source of light. This morphogenic property also oc- curs in animal cells, in which serotonin alters the cytoskeleton of cells and thus influences the formation of contacts. In addi- tion, serotonin regulates cell proliferation, migration and mat- uration in a variety of cell types, including lung, kidney, endo- thelial cells, mast cells, neurons and astrocytes). In brain, serotonin has interactions with seven families of receptors, numbering at least 14 distinct proteins. Of these, two receptors are important for the purposes of this review. These are the 5-HT1A and 5-HT2A receptors, which in fact have opposing functions in a variety of cellular and behavioral processes. The 5-HT1A receptor develops early in the CNS and is associated with secretion of S-100 from astrocytes and reduction of c- AMP levels in neurons. These actions provide intracellular sta- bility for the cytoskeleton and result in cell differentiation and cessation of proliferation. Clinically, 5-HT1A receptor drugs de- crease brain activity and act as anxiolytics. The 5-HT2A recep- tor develops more slowly and is associated with glycogenolysis in astrocytes and increased Ca  availability in neurons. These actions destabilize the internal cytoskeleton and result in cell proliferation, synaptogenesis, and apoptosis. In humans, 5-HT2A receptor drugs produce hallucinations. The dynamic interactions between the 5-HT1A and 5-HT2A receptors and the cytoskeleton may provide important insights into the etiology of brain disorders and provide novel strategies for their treatment. © 2001 Elsevier Science Inc. KEY WORDS: 5-HT1A, 5-HT2A, Receptor, Cytoskeleton, Protein kinase C (PKC), S-100, Astrocytes, BrdU. INTRODUCTION Serotonin has been implicated in more behaviors, physiological mechanisms, and disease processes than any other brain neuro- transmitter. The enormous range of this single brain chemical system may reflect the vast distribution of its fibers in brain, from a small group of large multipolar neurons. The neurons form a collection of clustered cells termed the raphe nuclei, located on the exact midline of the brainstem. Serotonergic fibers interact in complex ways with a variety of cell types—neurons, glial cells, endothelial cells, ependymal cells and others— by binding to at least 14 distinct receptor proteins. Furthermore, serotonin neurons are one of the first brainstem neurons to emerge during early development of the brain and spinal cord—present by the sixth week of gestation in humans. In rats, 5-hydroxytryptamine (5-HT) neurons in the brainstem raphe are among the first neurons to differentiate in the brain and play a key role in regulating neuro- genesis [64]. The serotonin neurons are the first neuronal system to innervate the primordial cortical plate. During development, 5-HT fibers arrive at the cortical plate during the peak period of mitosis and maturation [42]. Lauder and Krebs [65] reported that para- chlorophenylalanine (PCPA), a 5-HT synthesis inhibitor, retarded neuronal maturation, while mild stress, a releaser of hormones, accelerated neuronal differentiation. These workers defined differ- entiation as the cessation of cell division measured by incorpora- tion of 3 H-thymidine. Since then, many other workers have shown a role for serotonin in neuronal differentiation, (e.g., [54,74] and references contained in Whitaker-Azmitia, this issue). Certainly, all these facts suggest a critical role for serotonin in brain function, but is there really something distinct about serotonin, as a chem- ical? Serotonin is synthesized from tryptophan, which contains an indole ring and a carboxyl-amide side-chain, similar to all amino acids. The indole ring, however, is unique in that it is composed of both a benzene ring and a secondary pentane ring having a central nitrogen. The indole ring, and therefore tryptophan itself, is capa- ble of absorbing light. In plants, tryptophan produces receptor proteins which harness light and thus produce biologically impor- tant molecules [61]. Chlorophyll, for example, captures light be- cause it contains tryptophan, and then generates ATP, reduced cofactors (NADH), and oxygen. This entire process is blocked if tryptophan is substituted with another amino acid [84]. Further- more, in plants tryptophan itself is converted into the tropic factor auxin, by removing the amide group to make indole-acetic acid. Auxin stimulates changes in cell shape and provides movement for plants. The position of the leaves is regulated by auxin, in order that they face the source of light energy, normally the sun (Fig. 1). Thus tryptophan plays a role in capturing energy and in the positioning of the plant to maximize light absorption. This biosyn- thetic interaction between tryptophan and light may be maintained throughout evolution. For example, in the mammalian brain, se- * Address for correspondence: Efrain C. Azmitia, Ph.D., 10-09 Main Building, 100 Washington Square East, New York, NY 10003, USA. E-mail: efrain.azmitia@nyu.edu Brain Research Bulletin, Vol. 56, No. 5, pp. 413– 424, 2001 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved 0361-9230/01/$–see front matter 413