Serotonin functions as a neurotransmitter in nerve systems of simple as well as complex animals. For example, in the roundworm ''C. elegans'', which feeds by grazing on bacteria, serotonin acts like a signal of positive life events i.e. finding a new grazing ground. When a well-fed worm feels bacteria on its cuticle, dopamine is released, which slows it down; if it is starved, serotonin also is released, which slows the animal down further. This mechanism increases the amount of time animals spend in the presence of food.
The released serotonin activates the muscles used for feeding, while octopamine suppresses them. Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability. Artificial depletion of serotonin or increase of octopamine cues behavior that is typical of a low-food environment: ''C. elegans'' becomes more active, and mating and egg-laying is suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal.
Serotonin is necessary for normal male mating behavior, and the inclination to leave food to search for a mate.
The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin-like signaling and the TGF beta signaling pathway, which control long-term adaption. Mutants lacking serotonin have a increased reproductive lifespan, they become obese and some of the animals arrest their development at a dormant larval state. In the fruitfly where insulin both regulates blood sugar and acts as a growth factor serotonergic neurons regulate the adult body size by affecting insulin secretion. Serotonin has also been identified as the trigger for swarm behavior in locusts.
How much food an animal gets depends on an animal's social rank since the stronger animals may steal food from the weaker. Thus serotonin is not only involved in the perception of food availability but also of social rank. If a lobster is injected with serotonin, it behaves like a dominant animal, while octopamine causes subordinate behavior.
A frightened crayfish flips its tail to flee, and the effect of serotonin on this behavior depends on the animal's social status. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. Social experience alters the proportion between different serotonin receptors that have opposing effects on the fight-or-flight response. The effect of 5-HT1 receptors predominates in subordinate animals while 5-HT2 receptors predominates in dominants.
In humans though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones so that serotonin suppresses insulin release from the beta cells in the pancreas, and exposure to SSRIs reduces fetal growth.
Serotonin levels is affected by diet in humans. An increase in the ratio of tryptophan to phenylalanine and leucine will increase serotonin levels. Fruits with a good ratio include dates, papaya and banana. Foods with a lower ratio inhibit the production of serotonin. These include whole wheat and rye bread. Research also suggests that eating a diet rich in whole grain carbohydrates and low in protein will increase serotonin by secreting insulin, which helps in amino acid competition.
However, increasing insulin for a long period of time may trigger the onset insulin resistance, obesity, type 2 diabetes, and lower serotonin levels.
Muscles use many of the amino acids except tryptophan, allowing men to have more serotonin than women. Myo-inositol, a carbocyclic polyol present in many foods, is known to play a role in serotonin modulation.
Serotonin also has effects on appetite, sleep and general metabolism. In the blood, the major storage site is platelets, which collect serotonin from plasma. Bleeding causes serotonin release, which constricts blood vessels.
Irritants present in food trigger the enterochromaffin cells to release serotonin to increase peristaltic movements for emptying of the gut. Leakage of intestinal serotonin into the bloodstream at a rate faster than the platelets can absorb it increases free serotonin in the blood, which activates 5HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting.
In the ultimatum game, participants whose serotonin levels have been artificially lowered will reject unfair offers more often than players with normal serotonin levels.
In humans since levels of 5-HT1A receptor activation in the brain show negative correlation with aggression, and a mutation in the gene that codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.
Serotonergic signaling plays an important role in the modulation of human mood, anger and aggression. Individuals of ''C.elegans'' facing stress (eg. a low-food environment) resume normal behavior if given serotonin-increasing drugs. The same drugs have similar effects in humans; the action of serotonin on the worms' mating and egg-laying resembles its effects on human sexuality.
Serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors. Serotonin present in the blood then stimulates cellular growth to repair liver damage.
5HT2B receptors also activate osteoblasts, which build up bone However, serotonin also activates osteoclasts, which degrade bone.
Serotonin in addition evokes endothelial nitric oxide synthase activation and stimulates through a 5-HT1B receptor meditated mechanism the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures. Serotonin has broad activities in the brain, and genetic variation in serotonin receptors and the serotonin transporter, which facilitates re-uptake of serotonin into presynapses, have been implicated in neurological diseases. Drugs targeting serotonin-induced pathways are being used in the treatment of many psychiatric disorders. One focus of clinical research is the influence of genetics on serotonin action and metabolism in psychiatric settings. Such studies have revealed that the variation in the promoter region of the serotonin transporter protein accounts for nearly 10% of total variance in anxiety-related personality, and the effect of this gene on depression was found to interact with the environment.
Serotonin can also be altered by the amount of time spent in natural sunlight. Bright light therapy may have an effect on blood serotonin levels. Recently, acupuncture has been shown to stimulate the release of serotonin in lab animals.
Several toad venoms, as well as that of the Brazilian wandering spider and stingray, contain serotonin and related tryptamines.
Serotonin in the central nervous system is not essential to viability in some mammals, as shown for mice that are genetically altered so that they are unable to produce serotonin in the brain stem. These mice can live into adulthood and even give birth to live pups. Although brain serotonin is not essential for viability, its ablation causes impairment such as growth retardation, 50% mortality in the first four weeks of postnatal life, and effects on various physiological and behavioral pathways that originate from the autonomic nervous system. Specifically, mice dams that lack serotonin in the brain are less able to rear pups and show more aggression towards other mice.
The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation.
Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching large areas of the brain. Axons of neurons in the ''caudal'' raphe nuclei terminate in the following locations:
- Deep cerebellar nuclei
- Cerebellar cortex
- Spinal cord
On the other hand, axons of neurons in the ''rostral'' raphe nuclei terminate in e.g.:
Thus, activation of this serotonin system has effects on large areas of the brain.
Serotonin is released from serotonergic varicosities (swellings) into the extra neuronal space, but not from synaptic terminal boutons as other neurotransmitters. Serotonin diffuses over a relatively wide gap (>20 µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.
5-HT receptors are the receptors for serotonin. They 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 hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or ''heptahelical'') receptors that activate an intracellular second messenger cascade.
Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).
Interestingly, a 2006 study conducted by the University of Washington suggested that a newly discovered monoamine transporter, known as PMAT, may account for "a significant percentage of 5-HT clearance". Contrasting with the high-affinity SERT, the PMAT has been identified as a low affinity transporter with an apparent Km of 114 micromoles/L for serotonin; 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 some SSRIs, such as fluoxetine and sertraline, inhibit PMAT but at IC50 values which surpass the therapeutic plasma concentrations by up to four orders of magnitudes; therefore, SSRI monotherapy is ''ineffective'' in PMAT inhibition. At present, there are no known pharmaceuticals which would appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine albeit at Km values even higher than that of 5-HT (330–15,000 μmoles/L).
Serotonin can also signal through a nonreceptor mechanism called serotonylation. In this serotonin modifies proteins. A similar process underlies the pancreatic release of insulin.
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