Serotonin

Serotonin, also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with widespread functions in both the central nervous system (CNS) and peripheral tissues. It plays essential roles in mood regulation, cognition, learning, memory, reward processing and several physiological functions including vomiting, vasoconstriction and gastrointestinal motility. Beyond its neurological roles, serotonin contributes to vascular regulation, hemostasis and immune responses. It is present in almost all bilateral animals, as well as in fungi and plants, where it serves defensive and signalling functions.

Biosynthesis and Molecular Features

Biochemically, serotonin is an indoleamine synthesised from the essential amino acid tryptophan. The rate-limiting step is the hydroxylation of tryptophan by tryptophan hydroxylase, producing 5-hydroxytryptophan, which is then decarboxylated by aromatic L-amino acid decarboxylase to form serotonin. Structurally, the serotonin molecule can adopt several conformations due to rotation around its ethylamine side chain. Crystallised serotonin adopts the orthorhombic space group P2₁2₁2₁ and exhibits a hydrogen-bonding network involving N–H···O and O–H···N interactions. Serotonin forms various salts, including pharmaceutical formulations such as serotonin adipate.

Distribution in the Body

The majority of the body’s serotonin—approximately 90%—is synthesised in the gastrointestinal tract by enterochromaffin cells, where it regulates intestinal motility. Smaller amounts are produced in the raphe nuclei of the brainstem, the skin’s Merkel cells, pulmonary neuroendocrine cells and taste receptor cells. After release from enterochromaffin cells, serotonin is taken up by circulating platelets, which store around 8% of total body serotonin and release it during clot formation. Approximately 12% of the body’s serotonin is located within the CNS.
In addition to its presence in animals, serotonin occurs in plants, fungi and some protozoa. In plants and insect venoms, it often induces pain or irritation as a defensive mechanism. Certain pathogenic amoebae release serotonin in the human gut, contributing to diarrhoeal symptoms.

Physiological and Behavioural Roles

Serotonin influences an extensive range of biological and behavioural processes. In the brain, it regulates mood, appetite, circadian rhythms, sleep and thermoregulation, while also shaping learning, memory and reward pathways. It contributes to pain modulation and social behaviour, and plays an important role in sexual function and motor activity. In development, serotonin influences neural growth, synaptic formation and early patterning of neural circuits.
In less complex organisms, including various invertebrates, serotonin modulates feeding, locomotion and behavioural responses to environmental stimuli. In plants, elevated serotonin levels are associated with stress responses such as mechanical injury or pathogen attack.
Despite its prominence in popular discussions of mental health, the longstanding claim that depression results directly from low serotonin levels is not supported by conclusive scientific evidence. Nonetheless, serotonin remains a major target of pharmacological treatments for mood and anxiety disorders.

Serotonergic System in the Nervous System

The raphe nuclei, located along the midline of the brainstem, constitute the primary source of serotonin in the CNS. These nuclei (B1–B9) send ascending projections to the cerebrum, limbic system and cortex, and descending pathways to the cerebellum and spinal cord. This widespread connectivity allows serotonin to modulate diverse neural circuits and influence global brain states.
The serotonergic system interacts closely with other neurotransmitter pathways, including dopaminergic systems such as those originating in the ventral tegmental area and substantia nigra. These interactions contribute to effects on reward, motivation and motor control.

Metabolism and Termination

Serotonin is broken down primarily by monoamine oxidase (MAO), which converts it into 5-hydroxyindoleacetaldehyde. This intermediate is then oxidised by aldehyde dehydrogenase (ALDH) to produce 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite excreted by the kidneys.
Termination of serotonergic signalling occurs mainly through reuptake into presynaptic neurons by the serotonin transporter (SERT). Several pharmacological agents—including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, cocaine and certain cough suppressants—block this transporter and thereby elevate synaptic serotonin levels.
A secondary transport mechanism involves the plasma membrane monoamine transporter (PMAT), a low-affinity but high-capacity transporter contributing to clearance under conditions of elevated extracellular serotonin. High doses of SSRIs may partially inhibit PMAT in addition to their effects on SERT.
In addition to receptor-mediated signalling, serotonin can affect cellular function through serotonylation, a process in which serotonin covalently modifies intracellular proteins. This mechanism influences platelet activation, insulin release and vascular smooth muscle contraction.

Receptors

Serotonin acts through a diverse family of 14 known receptor subtypes, designated 5-HT₁ through 5-HT₇, with several further subdivisions:
• 5-HT₁ family: 1A, 1B, 1D, 1E, 1F• 5-HT₂ family: 2A, 2B, 2C• 5-HT₃ receptor (a ligand-gated ion channel)• 5-HT₄, 5-HT₅ (5A, 5B), 5-HT₆ and 5-HT₇ receptors
With the exception of 5-HT₃, all serotonin receptors are G-protein-coupled receptors (GPCRs), activating second-messenger cascades when stimulated. The 5-HT₅B receptor is present in rodents but absent in humans. Serotonin also acts as an agonist at the trace amine-associated receptor 1 (TAAR1) in several species, though its effectiveness at this receptor varies considerably.
Structural studies using cryo-electron microscopy have revealed detailed ligand–receptor complexes of the 5-HT₂A receptor with serotonin and various serotonergic psychedelics, advancing understanding of receptor activation mechanisms.

Pharmacological Significance

Many antidepressants and anxiolytics act on serotonergic systems, primarily through inhibition of SERT or modulation of receptor activity. Selective serotonin reuptake inhibitors (SSRIs) and serotonin–noradrenaline reuptake inhibitors (SNRIs) remain widely used for mood disorders. Other agents, including psychedelics and atypical antipsychotics, produce characteristic psychological effects through actions on specific 5-HT receptors.
Serotonin’s dual role in vasoconstriction and vasodilation makes it significant in cardiovascular physiology, platelets, and vascular smooth muscle. Its impact on gastrointestinal motility underlies several treatments for gut disorders and helps explain symptoms in certain infections.