What is Serotonin and What Does It Do?

What is Serotonin?

Also called 5-hydroxytryptamine (5-HT), serotonin is a monoamine neurotransmitter. It is found throughout the body, with only a relatively small portion present in the brain. It cannot cross the blood-brain barrier and must be produced within the brain through a process described below. The original meaning of the word serotonin is a serum that gives tone. It referred to the serotonergic action outside of the CNS - causing contraction of smooth muscle. Yet, within the central nervous system it is involved in functions such as arousal, thermoregulation, mood, appetite, sleep and pain regulatory systems. Serotonin's effects are normally inhibitory. It diminishes appetite, sexual behavior and suppresses pain perception. Its absence has been correlated with an increase of aggressive behavior. There is a strong correlation between serotonin levels and aggression, irritability, and impulsivity (validated by diverse psychological tests such as the Buss-Durkee Hostility inventory). Also, serotonin levels have been correlated with disordered eating patterns and sleep disorders. A close relationship has been found between the serotonergic system and the noradrenergic system; the areas where they interact appear to greatly influence an individual's behavior. The relationship functions as seen in the following table (Siever, 1997):

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Where Does It Act?

60 to 75% of the brain's 5-HT is found within the nine main serotonergic nuclei. The first of these is found on the ventral surface of the pyramidal tract. The second is found at the nucleus raphe obscurans, at the raphe at the level of the hypoglossal nucleus. The third receptor nucleus is found at the level of the facial nerve nucleus, surrounding the pyramidal tract. The fourth nucleus is located at the floor of the fourth ventricle, dorsal to the abducens nuclei. A small fifth nucleus is found at the pontine raphe nucleus while below the ependyma, towards the rostrum of the fourth ventricle, a sixth nucleus is located. An important and relatively large seventh nucleus is located above and between the longitudinal fasiculi at the central substantia grisea. The medial raphe nucleus includes the eighth serotonergic receptor nucleus. The ninth group is found at the medial lemniscus nucleus, it includes fibers from the mesencephalic raphe towards the neostriatum.(Essman, 1980)

The following image illustrates the circuit in the rat's brain:

The aforementioned nuclei are part of diverse pathways that form the serotonergic circuit. The ascending pathways are as follows: There is a medial pathway that originates at the mesencephalic raphe nuclei and the pontine raphe region and innervates the hypothalamus and the preoptic region. It also allows innervations to the nucleus suprachiasmaticus, some amygdaloid nuclei, the ventral region of the lateral geniculate body, septal and preoptic areas, anterior culliculi and the hippocampal formation. There is also a lateral ascending pathway originating at the mesencephalic raphe nuclei and innervating the mesocortex and neocortex. Then a far lateral pathway, (also originating at the mesencephalic raphe nuclei), projects to the extrapyramidal motor nuclei. A cerebral innervation pathway originates at the mesencephalus and the pons. The descending fibers originate mainly at the nucleus raphe obscurus and the nucleus raphe pallidus, as well as at the third serotonergic nucleus, and they extend many collaterals towards the gray matter of the spinal chord; the lumbosacral section receives a particularly large number of fibers. On a side note, it should be mentioned that many of the serotonin cell bodies in the medulla oblongata are innervated by norepinephrine-containing nerve terminals. Morphologically speaking, there are two main kinds of serotonergic axonal fibers, the D and the M systems. The D system, which originates at the median raphe nucleus, is formed by thin axonal fibers. The M system projects from the median raphe nucleus and is formed by thick axonal fibers (Hockman, 1976).

Nine different types of serotonergic receptors have been identified: 5-HT 1A, 1B, 1D, 1E, 1F, 2A, 2B, 2C and 5-HT 3.

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How Does It Work?

Serotonin is produced within the neurons. It is a result of the hydroxylation of a tryptophan molecule by tryptophan hydroxylase, followed by the decarboxilation of the resulting 5-hydroxytryptophan by 5-htp decarboxylase. The original tryptophan molecule is an amino acid that cannot be produced within the body; it must be ingested. After the 5-HT has been produced at the soma of the neuron and enveloped in vesicles at the Golgi apparati, they are carried by axoplasmic transport to axonal varicosities, or swellings of the axon. If the axon is part of the D system, it will release the 5-HT freely to diffuse out to the neighboring regions; it does not form a definite synapse. If the axon is part of the M system, it will release the 5-HT into a synaptic cleft, where it will travel to the postsynaptic membrane at which 5-HT receptors 1B, 1D, 1E, 1F, 2A, 2B, 2C and 5-HT 3 will attach to it. The release of 5-HT may occur under resting conditions. The attachment of the serotonin to the receptors will produce an inhibitory action upon the postsynaptic cell (IPSP) in two ways: metabotropically and ionotropically. The metabotropic process includes receptors 1B, 1D, 1E, 1F, 2A, 2B, and 2C. It hyperpolarizes the postsynaptic cell indirectly via a metabolic process initiated by the attachment of the 5-HT. The ionotropic receptor, 5-HT 3, directly controls a chloride channel and therefore produces direct IPSPs. Within the presynaptic cell, monoamine oxidase will deactivate serotonin if the levels are too high. Another autoregulatory process is that of negative feedback. The 5-HT1A receptor is a presynaptic receptor that detects high levels of serotonin at the synaptic cleft. It will discontinue the release of 5-HT if the levels are too high. After a certain time has passed, the serotonin is reabsorbed by the presynaptic cell through the process of reuptake (Carlson, 2001).

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Serotonin and Drugs

The drugs used in relation to serotonin act on it mainly in the following ways: Interfering with reuptake; deactivating serotonin before release from the presynaptic cell; interfering with the process of serotonin synthesis; interfering with the binding of 5-HT to its postsynaptic receptors or presynaptic receptors; or substituting the 5-HT to bind with the receptors. The following image might help to understand how drugs act on neurotransmitters: