Neural activity in its simplest form is an action potential. These phenomena propagate to the end of pre-synaptic neurons via voltage-gated channels, which reconfigure themselves just enough to allow sodium ions to rush in from the sodium chloride salt solution surrounding the neuron. These ions obey physical laws of electrical and concentration gradients as they mindlessly push a slight membrane potential down the length of an axon towards the synapse. It may seem that the cascade of charge that brought the action potential to the synapse is where the drama of human cognition resides. An action potential, however, is simply the foregone conclusion of a cell reaching equilibrium in a salt solution. An action potential is an all or nothing event. It is not until the encoded message has reached the 30 or 40 nm gap of the synapse that the imponderably dense tapestry of human thought occurs. Pre-synaptic neurons release complex molecules known as neurotransmitters to propagate the messages from their action potentials to post-synaptic neurons. These neurotransmitters, once released into the synapse by exocytosis, bind to post-synaptic receptors in order to either inhibit or excite an action potential in the post-synaptic cell. These neurotransmitters range from the relatively well known such as endorphin and epinephrine (adrenaline) to the obscure such as N-Acetylaspartylglutamate and substance P.
Mechanisms and Anatomy
One of the most enigmatic neurotransmitters is serotonin, a monoamine usually found in the gastrointestinal (GI) tract and the central nervous system (CNS) of both humans and animals. The term monoamine refers to a group of neurotransmitters and neuromodulators that contain one amino group that is connected to an aromatic ring by a two-carbon chain (1).
Neurotransmitters rely on cellular receptors to convey their intended effect to the interior of the target cell. The receptors specific to serotonin are known as 5-HT receptors. These receptors are found in the form of both G-protein coupled receptors and ligand-gated channels. Once serotonin binds to these receptors, secondary messenger cascades are activated in order to either inhibit or excite a desired effect in the cell. In addition, many illicit drugs including hallucinogens and entactogens are designed to bind to 5-HT receptors in order to artificially produce the intended effects of serotonin (2,3).
Because almost 80 percent of the human body’s total serotonin is located in the enterochromaffin cells, which belong to a group of hormone-producing cells known as enteroendocrine cells in the lumen of the GI tract, serotonin has a large role in regulating intestinal movements (1,4). The remainder of the body’s serotonin, however, is synthesized in the CNS where it has various functions including regulating mood, appetite, sleep, muscle contraction, and some cognitive functions including memory and learning (1).
Mood
One of serotonin’s most profound neurological functions is its regulation of an individual’s feeling of wellbeing. It is for this reason that modulation of serotonin within the synapse is the major action of several different classes of pharmacological antidepressants (1,3). The most effective of these drugs within recent years have the medical title Selective Serotonin Reuptake Inhibitors (SSRI), because of their role in keeping serotonin within the synaptic cleft, rather than allowing it to be exposed to re-uptake by the pre-synaptic neuron (3). The three basic molecules, which are all monoamines like serotonin that are thought to play a role in mood-regulation are norepinephrine, serotonin, and dopamine (1,3). It was originally postulated that an excess of norepinephrine caused mania, and that the absence of norepinephrine caused depression. However, mood change was not seen in every subject that was exposed to changes in epinephrine. It was Arthur J. Prange, Jr. who first introduced the idea with his “permissive hypothesis” that stated that a synaptic depletion of serotonin caused depression by “permitting” a fall in norepinephrine levels. Consequently, although norepinephrine obviously still plays the dominant role in depression, it is serotonin that is the original regulator, and thus it is serotonin that has become, as previously mentioned, the target of antidepressant drugs (3).
Behavioral Effects
Another important role that serotonin has in the regulation of animal behavior involves competition and aggressiveness (1,5). It was found that lobsters injected with serotonin demonstrate dominant attributes, especially in the context of food acquisition. Conversely, octopamine, when injected into the lobsters, was found to have a submissive effect. Interestingly, the effect that serotonin has on an animal’s aggressiveness is not a direct relationship. Highly socially ranked crayfish, when injected with serotonin and frightened, will be more apt to flee. However, subordinate crayfish under the same fear and serotonin exposure will exhibit inhibited fear response. Research indicates that the reason for this difference in reaction involves serotonin receptors (5H-T receptors) and how they are shaped by social experience (1). It would appear that altering the proportion between different 5H-T receptors that have opposing effects on the flight-or-fight response is responsible for the different expression of serotonin in the face of similar social stimuli such as fear. Specifically, the effect of 5-HT1 receptors predominates in subordinate animals, while 5-HT2 receptors are more common in dominant animals. Both of the 5-HT receptors are a class of G-protein coupled receptors, which exhibit both Gi and Go sub-units. The 5-HT1 receptors mediate inhibitory neurotransmission, while the 5-HT2 mediate excitatory neurotransmission.
Regulation of Body Size
Serotonin also has a role in regulating both total body size and tissue growth in certain organs (6). It has been found that in insects insulin both regulates blood sugar and acts as a growth factor. Thus, because serotonergic neurons control secretion of this hormone, insect body size is directed by serotonin. The situation is slightly different in humans. Although insulin still regulates blood sugar, insulin-like growth factor regulates growth (6). However, because serotonin controls the release of both of these hormones, it can still be deemed a regulating factor for both blood sugar and growth. The specifics of serotonin’s role in regulation of blood sugar involve suppressing the release of insulin, which is secreted from the beta cells in the pancreas. Thus, serotonin increases blood glucose by inhibiting the cell-sequestering effect that insulin has on sugar (6). In terms of human body size, it has been found that exposure to SSRIs, which are mentioned earlier, reduces fetal growth. Human serotonin can also act as a growth factor directly. The liver is one organ in which the direct impact of serotonin on cellular growth is most apparent (6). Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors. Once these receptors are present, the cells are able to receive serotonin in the blood. Blood-bourne serotonin then stimulates cellular growth to repair liver damage. Serotonin also has a relationship with bone growth (6). Serotonin-sensitive 5-HT2B receptors activate osteoblasts, which build up bone. Interestingly, however, serotonin is also responsible for activating osteoclasts, which degrade bone.
- Molecular structure of serotonin
Relation to Drug Use
As previously stated, many psychedelic and hallucinogenic drugs mimic serotonin by binding to 5-HT receptors. Most of these drugs are chemically categorized as tryptamines, which are monoamine alkaloids. One example is psilocin, which is a psychedelic mushroom alkaloid (7). Along with its phosphorylated counterpart, psilocybin, psilocin is found in most psychedelic mushrooms. Upon consumption, almost all of the mushroom’s psilocybin is rapidly dephosphorylated to psilocin, which then acts as a 5-HT2A, 5-HT2C and 5-HT1A agonist, which means that its structural similarity to serotonin allows it to bind to the aforementioned 5-HT receptors. Some of the symptoms of ingestion of psilocin include tachycardia, dilated pupils, euphoria, open and closed eye visuals, and temporary synesthesia.
Another prominent drug that is a serotonin analogue is Dimethyltryptamine (DMT), which is a naturally occurring tryptamine (7). This drug is found in trace amounts in the human body, but its biological role is currently unknown (7). DMT is an agonist of the 5-HT2A receptor and is capable of activating the 5-HT2C receptor as well (7). Thus, it is similar to psilocin in terms of its mechanism of cellular activation. DMT ingestion provides some of the same effects as psilocin, such as visuals and euphoria. DMT is also capable of producing strong hallucinations and even religious experiences.
Probably the most well known drug that exhibits serotonin agonistic properties is Lysergic acid diethylamide (LSD) (2). LSD is a tryptamine like the two drugs described above, and it binds to almost all of the serotonin receptors (2).
The euphoric, psychedelic and sympathetic effects of these and other serotonin drugs are potential windows into understanding the action of serotonin itself. In fact, overdose with or often even the normal action of these drugs can lead to a condition known as “serotonin syndrome” (3).
Serotonin Syndrome
Because serotonin syndrome is not an idiosyncratic drug reaction, but rather a predictable effect of elevated serotonergic activity, it is useful for studying serotonin’s effects on the human body (3). Aside from exaggerated expressions of the normal effects of the above-listed drugs, serotonin syndrome can exhibit life-threatening symptoms such as extremely elevated body temperature (>106 °F), highly elevated heart rate and blood pressure, lowered blood pH (metabolic acidosis), a rapid breakdown of skeletal muscle (rhabdomyolysis), and even a pathological over-activation of blood clotting mechanisms (disseminated intravascular coagulation) (3). Most of these are either caused or exacerbated by hyperthermia brought on by the serotonin agonist drugs’ sympathetic activity on the CNS (3).
Serotonin syndrome is usually the result of several synergistically operating serotonin agonists, or a serotonin agonist in the presence of a monoamine oxidase inhibitor (MAOI) (3). As previously stated, serotonin is a monoamine, which is a class of organic molecule that can be degraded by monoamine oxidase. Thus, in the presence of a MAOI, synaptic serotonergic activity can spiral out of control with as much efficacy as multiple serotonin agonists working in concert. Research suggests that the serotonin receptor most apt to contribute to serotonin syndrome is the 5-HT2A receptor (3).
Conclusion
Serotonin pathway shown in red
Neurotransmitters are one of the most profound links between the subjective human experience and the chemical reality of the physical world. Their elegant molecular bends and shapes craft individuals at the most essential level. Although scientists are working ceaselessly to illuminate the roles that these silent messengers play, their roles may be irrevocably intertwined. It could well be that oxytocin gives rise to amorous feelings, which approach love, or that substance P is truly the mediator of human physical pain, but the brain does not perceive these chemicals in a vacuum. The impenetrable complexity, and arguably the ineffable beauty of the human condition is more than likely a synergistic interplay of the spectrum of neurotransmitters, rather than a one-to-one ratio of role to chemical.
Serotonin provides humans with a choice. It is essential in preventing depression, but it is also the gatekeeper of mania. It is as mechanically practical in the GI tract as it is inscrutably human in its role in the regulation of social hierarchies. It holds applications for both responsible drug use such as in SSRIs, and for the unbridled psychedelic fringes of chemical intake with LSD, DMT, and psilocin mushrooms.
It is for these reasons that serotonin is a paragon of the relationship between human beings and their neurotransmitters. It bridges the gap between the sterile chemical realm and the integrated tapestry of human experience by hovering forever between the extremes of biological function.
References
1. L. R. Mandel, R. Prasad, B. Lopez-Ramos, R. W. Walker. Research Communications in Chemical Pathology and Pharmacology. 47-58 (1977).
2. “MeSH Descriptor Data: National Library of Medicine.” (Tech. Rep. National
3. M. W. King. “Table of Neurotransmitters: The Medical Biochemistry Page.” (Tech. Rep., Indiana University, Bloomington, 2010).
4. D. Gunnell. Official Journal of the American Academy of Pediatrics. 681-86 (2005).
5. K. P. Lesch. Science 274.5292 1527-531 (1996).
6. G. Aghajanian O. Bing. Clinical pharmacology therapy. 611-15 (1964)
7. K. P. Gillman. Biological Psychiatry. 1046-051 (2006).
John Beiv
Hm.. really interesting article.. Like it! =)