Serotonin

Also known as: 5-HT, 5-hydroxytryptamine, serotonin function, what does serotonin do, serotonin vs dopamine, serotonin and dopamine

In one sentenceSerotonin (5-HT) is a chemical messenger made by brainstem neurons and by cells lining the gut. In the brain it helps regulate mood, sleep, appetite and many other behaviors.

What does serotonin do?

Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter: a chemical that neurons release at a synapse to pass signals to other cells. In the brain its classically defined roles are in the control of mood, sleep and anxiety, and a 2009 review lists mood, perception, reward, anger, aggression, appetite, memory, sexuality and attention among the behaviors it modulates. Most of the body’s serotonin, however, is made outside the brain, in the gut, where it helps control bowel movement; it also affects platelet function and the cardiovascular system. Each point is set out below.

Where serotonin is made

Serotonin is made from tryptophan, an essential amino acid. The rate-limiting step is carried out by the enzyme tryptophan hydroxylase (TPH), which comes in two forms in different cells. TPH1 is found mainly in enterochromaffin cells, specialized hormone-releasing cells in the lining of the gut. TPH2 is found mainly in neurons of the raphe nuclei in the brainstem, and in a subset of neurons of the gut’s own nervous system. Because serotonin cannot readily cross the blood–brain barrier, the brain’s serotonin and the serotonin in the rest of the body form two separate pools that act in their own ways.

In the gut

Roughly 95% of the body’s serotonin is released in the gut by enterochromaffin cells, according to a 2009 review by Miles Berger, John Gray and Bryan Roth. Gut bacteria influence how much is made. In 2015 Jessica Yano, Elaine Hsiao and colleagues showed that spore-forming bacteria from the mouse and human gut microbiota promote serotonin production by enterochromaffin cells in the colon. In mice, these bacteria-dependent changes in gut serotonin affected gut motility and platelet function.

In the brain

Fewer than one in a million neurons in the central nervous system produce serotonin. They lie in the raphe nuclei, clusters of cells near the midline of the brainstem. A rostral group in the midbrain and upper pons, including the dorsal and median raphe nuclei, sends its axons mainly to the forebrain. A caudal group in the lower pons and medulla projects to other brainstem nuclei and to the spinal cord. Serotonergic axons branch over large areas: some form classical chemical synapses, while many do not and instead release serotonin more diffusely, a mode called volume transmission. Every brain region carries several types of serotonin receptor.

Serotonin receptors

Serotonin acts through at least 13 G protein-coupled receptors plus the 5-HT3 receptor, which is a ligand-gated ion channel. They are divided into seven classes, 5-HT1 to 5-HT7. A single neuron can carry receptors with opposite effects: layer V pyramidal neurons of the cerebral cortex have both 5-HT1A and 5-HT2A receptors, which push their firing in opposite directions. Nearly all serotonin receptors are found outside the brain as well as inside it. Berger and colleagues argue that because brainstem serotonin neurons reach so many brain circuits, and every region carries receptors, serotonin can influence a very wide range of behaviors.

Serotonin and waiting

Optogenetics, which uses light to switch on chosen neurons, has let researchers test what serotonin neurons do in behaving animals.

• In 2014 Kayoko Miyazaki, Kenji Doya and colleagues activated serotonin neurons in the dorsal raphe nucleus of mice during a task with delayed food rewards. Stimulation reduced how often mice gave up waiting too early, and when the reward was withheld, stimulated mice waited longer. Control experiments indicated that the effect was not due to motor inhibition, general behavioral inhibition or a rewarding effect of the stimulation.
• In 2015 Madalena Fonseca, Masayoshi Murakami and Zachary Mainen found that the same kind of stimulation increased, in a dose-dependent way, mice’s ability to hold back premature responses while waiting several seconds for a randomly delayed tone. In place-preference and value-based choice tests, they found no sign that the stimulation was either appealing or aversive to the mice.

Not every study agrees that these neurons are neutral about reward. In 2014 Zhixiang Liu, Minmin Luo and colleagues stimulated dorsal raphe neurons defined by the gene Pet-1, a population usually associated with serotonin. The stimulation reinforced behavior: mice explored the place where they were stimulated and stimulated themselves when given the chance. These neurons release glutamate as well as serotonin, and both chemicals contributed to the reward signal.

Serotonin vs dopamine

Serotonin and dopamine are often discussed together, and researchers have long asked how the two systems relate.

Building on the idea that dopamine neurons signal reward prediction errors, Nathaniel Daw, Sham Kakade and Peter Dayan proposed in 2002 that the dorsal raphe serotonin system and the midbrain dopamine system may act as mutual opponents, and speculated that a brief (phasic) serotonin signal might report a prediction error for future punishment. A 2011 review by Y-Lan Boureau and Dayan noted ample evidence for dopamine’s role on the reward side but little agreement about whether serotonin acts as an aversive opponent, or how.

The optogenetic studies above pushed against the simple opponent picture. Miyazaki and colleagues contrasted the classic theory, in which serotonin opposes dopamine and inhibits behavior when aversive events are predicted, with a more recent one in which serotonin supports long-term optimal behavior and suppresses impulsive behavior, and designed their experiment to test the two; activating serotonin neurons promoted patience. Liu and colleagues reported that dorsal raphe neurons encoded reward, not punishment.

A debated link to depression

The serotonin hypothesis of depression, the idea that depression is linked to lowered serotonin, has been influential. In 2022 Joanna Moncrieff and colleagues published an umbrella review of 17 studies, most of them systematic reviews and meta-analyses. They concluded that the main areas of serotonin research provide no consistent evidence of an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.

In 2023 a group of 35 researchers led by Sameer Jauhar disputed the review’s methods and conclusions. They argued that studies of acute tryptophan depletion and of decreased plasma tryptophan in depression indicate a role for serotonin in people vulnerable to or suffering from depression, and that molecular imaging suggests the system is perturbed. The question remains under debate. This article describes the research only and is not medical advice.

History

In the 1930s Vittorio Erspamer found a substance in the gut, which he called enteramine. In 1948 Maurice Rapport, Arda Green and Irvine Page isolated a substance from blood serum that constricts blood vessels and named it serotonin; Rapport identified its structure as 5-hydroxytryptamine in 1949. In 1952 Erspamer and Asero showed that enteramine was the same molecule.

Its detection as a neurotransmitter in invertebrates suggested that it might also occur in the vertebrate brain, and in 1953 it was found in the brains of dogs, rats and rabbits. From 1962 the Falck–Hillarp technique made serotonin neurons visible as fluorescent structures.