Serotonin

Serotonin, also known as 5-hydroxytryptamine, is a monoamine neurotransmitter with a wide range of functions in both the central nervous system and also peripheral tissues. It is involved in mood, cognition, reward, learning, memory, and physiological processes such as vomiting and vasoconstriction. In the CNS, serotonin regulates mood, appetite, and sleep.
Most of the body's serotonin—about 90%—is synthesized in the gastrointestinal tract by enterochromaffin cells, where it regulates intestinal movements. It is also produced in smaller amounts in the brainstem's raphe nuclei, the skin's Merkel cells, pulmonary neuroendocrine cells, and taste receptor cells of the tongue. Once secreted, serotonin is taken up by platelets in the blood, which release it during clotting to promote vasoconstriction and platelet aggregation. Around 8% of the body's serotonin is stored in platelets, and 1–2% is found in the CNS.
Serotonin acts as both a vasoconstrictor and vasodilator depending on concentration and context, influencing hemostasis and blood pressure regulation. It plays a role in stimulating myenteric neurons and enhancing gastrointestinal motility through uptake and release cycles in platelets and surrounding tissue. Biochemically, serotonin is an indoleamine synthesized from tryptophan and metabolized primarily in the liver to 5-hydroxyindoleacetic acid.
Serotonin is targeted by several classes of antidepressants, including selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors, which block reabsorption in the synapse to elevate its levels. It is found in nearly all bilateral animals, including insects, spiders and worms, and also occurs in fungi and plants. In plants and insect venom, it serves a defensive function by inducing pain. Serotonin released by pathogenic amoebae may cause diarrhea in the human gut, while its presence in seeds and fruits is thought to stimulate digestion and facilitate seed dispersal.

Molecular structure

Biochemically, the indoleamine molecule derives from the amino acid tryptophan, via the hydroxylation of the 5 position on the ring, and then decarboxylation to produce serotonin. Preferable conformations are defined via ethylamine chain, resulting in six different conformations.

Crystal structure

Serotonin crystallizes in P2₁2₁2₁ chiral space group forming different hydrogen-bonding interactions between serotonin molecules via N-H...O and O-H...N intermolecular bonds. Serotonin also forms several salts, including pharmaceutical formulation of serotonin adipate.

Biological role

Serotonin is involved in numerous physiological processes, including sleep, thermoregulation, learning and memory, pain, behavior, sexual activity, feeding, motor activity, neural development, and biological rhythms. In less complex animals, such as some invertebrates, serotonin regulates feeding and other processes. In plants serotonin synthesis seems to be associated with stress signals. Despite its longstanding prominence in pharmaceutical advertising, the claim that low serotonin levels cause depression is not supported by scientific evidence.

Cellular effects

Serotonin primarily acts through its receptors and its effects depend on which cells and tissues express these receptors.
Metabolism involves first oxidation by monoamine oxidase to 5-hydroxyindoleacetaldehyde. The rate-limiting step is hydride transfer from serotonin to the flavin cofactor. There follows oxidation by aldehyde dehydrogenase to 5-hydroxyindoleacetic acid, the indole acetic-acid derivative. The latter is then excreted by the kidneys.

Receptors

The serotonin receptors are located on the cell membrane of nerve cells and other cell types in animals, and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and psychedelic drugs. There are currently 14known serotonin receptors, including the serotonin 5-HT₁, 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₅, 5-HT₆, and 5-HT₇ receptors. Except for the serotonin 5-HT₃ receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors that activate an intracellular second messenger cascade. The 5-HT_5B receptor is present in rodents but not in humans.
In addition to the serotonin receptors, serotonin is an agonist of the trace amine-associated receptor 1 in some species. It is a weak TAAR1 partial agonist in rats, but is inactive at the TAAR1 in mice and humans.
The cryo-EM structures of the serotonin 5-HT_2A receptor with serotonin, as well as with various serotonergic psychedelics, have been solved and published by Bryan L. Roth and colleagues.

Termination

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including cocaine, dextromethorphan, tricyclic antidepressants and selective serotonin reuptake inhibitors. A 2006 study found that a significant portion of 5-HT's synaptic clearance is due to the selective activity of the plasma membrane monoamine transporter which actively transports the molecule across the membrane and back into the presynaptic cell.
In contrast to the high affinity of SERT, the PMAT has been identified as a low-affinity transporter, with an apparent K_m of 114 micromoles/l for serotonin, which is approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport "capacity" than SERT, "resulting in roughly comparable uptake efficiencies to SERT... in heterologous expression systems." The study also suggests that the administration of SSRIs such as fluoxetine and sertraline may be associated with an inhibitory effect on PMAT activity when used at higher than normal dosages.

Serotonylation

Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins. This process underlies serotonin's effects upon platelet-forming cells in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis. A similar process underlies the pancreatic release of insulin.
The effects of serotonin upon vascular smooth muscle tonethe biological function after which serotonin was originally nameddepend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.

Nervous system

The neurons of the raphe nuclei are the principal source of 5-HT release in the brain. There are nine raphe nuclei, designated B1–B9, which contain the majority of serotonin-containing neurons, all of which are located along the midline of the brainstem, and centered on the reticular formation. Axons from the neurons of the raphe nuclei form a neurotransmitter system reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord, while the axons of the higher nuclei spread out in the entire brain.
It is the dorsal part of the raphe nucleus that contains neurons projecting to the central nervous system. Serotonin-releasing neurons in this area receive input from a large number of areas, notably from prefrontal cortex, lateral habenula, preoptic area, substantia nigra and amygdala. These neurons are thought to communicate the expectation of rewards in the near future, a quantity called state value in reinforcement learning.

Ultrastructure and function

The serotonin nuclei may also be divided into two main groups, the rostral and caudal containing three and four nuclei respectively. The rostral group consists of the caudal linear nuclei, the dorsal raphe nuclei and the median raphe nuclei, that project into multiple cortical and subcortical structures. The caudal group consists of the nucleus raphe magnus, raphe obscurus nucleus, raphe pallidus nucleus, and lateral medullary reticular formation, that project into the brainstem.
The serotonergic pathway is involved in sensorimotor function, with pathways projecting both into cortical, subcortical, and spinal areas involved in motor activity. Pharmacological manipulation suggests that serotonergic activity increases with motor activity while firing rates of serotonergic neurons increase with intense visual stimuli. Animal models suggest that kainate signaling negatively regulates serotonin actions in the retina, with possible implications for the control of the visual system. The descending projections form a pathway that inhibits pain called the "descending inhibitory pathway" that may be relevant to a disorder such as fibromyalgia, migraine, and other pain disorders, and the efficacy of antidepressants in them.
Serotonergic projections from the caudal nuclei are involved in regulating mood and emotion, and hypo- or hyper-serotonergic states may be involved in depression and sickness behavior.

Microanatomy

Serotonin is released into the synapse, or space between neurons, and diffuses over a relatively wide gap to activate 5-HT receptors located on the dendrites, cell bodies, and presynaptic terminals of adjacent neurons.
When humans smell food, dopamine is released to increase the appetite. But, unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead, the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs that block 5-HT_2C receptors make the body unable to recognize when it is no longer hungry or otherwise in need of nutrients, and are associated with weight gain, especially in people with a low number of receptors. The expression of 5-HT_2C receptors in the hippocampus follows a diurnal rhythm, just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.
In macaques, alpha males have twice the level of serotonin in the brain as subordinate males and females. Dominance status and CSF serotonin levels appear to be positively correlated. When dominant males were removed from such groups, subordinate males begin competing for dominance. Once new dominance hierarchies were established, serotonin levels of the new dominant individuals also increased to double those in subordinate males and females. The reason why serotonin levels are only high in dominant males, but not dominant females has not yet been established.
In humans, levels of 5-HT_1A receptor inhibition in the brain show negative correlation with aggression, and a mutation in the gene that codes for the 5-HT_2A receptor may double the risk of suicide for those with that genotype. Serotonin in the brain is not usually degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surfaces. Studies have revealed nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy.