Serotonin is a well-recognized chemical compound, frequently discussed in various contexts. The journey of its discovery, however, spans several decades and involves a progression of scientific investigations. This historical narrative traces how researchers gradually unveiled this substance, first identifying its presence in blood, then isolating and naming it, before determining its precise chemical structure, and finally, recognizing its significance within the brain.
Initial Clues in Blood
Early in the 20th century, scientists observed that blood serum contained a substance capable of constricting blood vessels. By the turn of the century, research had begun to suggest that blood platelets were the source of this previously unknown constricting agent.
Physiologist Irvine Page, in 1945, at the Cleveland Clinic, was actively investigating the causes of hypertension. His work led him to encounter an uncharacterized substance in blood samples. This substance consistently emerged when blood coagulated, and it exhibited the distinct physiological effect of causing muscles and blood vessels to contract.
Isolation and First Naming
The pursuit of this blood factor intensified when Maurice Rapport joined Irvine Page’s laboratory at the Cleveland Clinic in 1946. Rapport was tasked with isolating this constricting substance from blood serum. To aid in this complex biochemical separation, they collaborated with Arda Green, a physical biochemist.
Rapport successfully isolated crystals of the substance, obtaining the raw material from ox blood. In a 1948 paper, the team introduced their discovery and coined a new name for the compound: “serotonin.” This name was derived from “serum,” the blood component from which it was isolated, and “tonic,” referencing its ability to increase vascular tone or tension.
Unveiling the Chemical Structure
Following its isolation and naming, the next scientific endeavor involved deciphering the precise chemical makeup of serotonin. Maurice Rapport, working independently, identified its structure in 1948 and publishing his findings in 1949. He determined that the compound was 5-hydroxytryptamine, often abbreviated as 5-HT.
The structure of 5-hydroxytryptamine is characterized by a benzene ring containing a hydroxyl group and an amine group, derived biochemically from the amino acid tryptophan. This structural identification was later confirmed in 1951 when chemists Hamlin and Fischer synthesized serotonin for the first time. Furthermore, in 1952, it was established that a substance called “enteramine,” which had been discovered earlier by Vittorio Erspamer in the gut, was chemically identical to 5-hydroxytryptamine.
Serotonin’s Brain Connection
For a period after its initial discovery, serotonin was primarily understood as a peripheral substance involved in blood vessel constriction. However, this perception began to change with the independent investigations into its presence within the central nervous system. A breakthrough occurred when Betty Twarog, a researcher working in Irvine Page’s laboratory, started exploring the compound’s distribution.
Twarog, who had previously developed a sensitive bioassay using clam muscle, undertook the task of analyzing various mammalian tissues for serotonin content. She successfully detected serotonin in the brains of dogs, rats, and rabbits. These unexpected findings were published in 1953, marking a turning point in the understanding of serotonin’s biological relevance. Concurrently, John Gaddum also reported the presence of 5-HT in the brain in 1954. These discoveries broadened serotonin’s perceived role beyond a simple vasoconstrictor, laying foundational groundwork for the emerging field of brain chemistry.