By: Sofia Arreguin
Serotonin
What is Serotonin?
Along with dopamine and norepinephrine, serotonin is classified as a monoamine neurotransmitter, meaning it regulates attention, cognition, consciousness, and emotion. Generally referred to by its official name, 5-hydroxytryptamine (5-HT), serotonin is responsible for delivering messages from the brain’s nerve cells to the rest of the body, providing instructions for how its organs and other structures should function (Cleveland Clinic, 2022). Acting as a hormone, 5-HT helps to regulate an individual’s mood, digestion, nausea, bone health, hunger, memory, happiness, wound recovery, and sexual desire. For instance, serotonin provides emotional stability and focus, earning it its reputation of generating “happy” or “feel-good” sentiments. Further, when released into the blood, serotonin prompts arterioles, blood vessels, to constrict, slowing the flow of blood and contributing to the formation of blood clots, assisting in wound recovery.
Located within the central nervous system and, primarily condensed, within the gastrointestinal tract, specifically its enterchromaffin cells, the production of serotonin can be summarized into two steps. First, an essential amino acid named tryptophan is hydroxylated by an enzyme called tryptophan hydroxylase, meaning the hydroxyl group -OH is added, to form 5-hydroxytryptophan. Second, this 5-hydroxytryptophan (5-HTP) is decarboxylated, meaning the carboxyl group COOH was removed, to create serotonin, or 5-HT (Bakshi, A. & Tadi, P., 2022). Serotonin is then synthesized, or produced, and kept in presynaptic neurons within the central nervous system. Here, the processing of serotonin begins with the release of 5-HT into the synaptic cleft, the zone of communication between neurons, where they then bind to postsynaptic serotonin receptors or presynaptic serotonin autoreceptors. When bound to the postsynaptic receptor, its activation produces a signal that either inhibits or excites the receiving neuron; in presynaptic receptors, the release of serotonin is regulated, reducing 5-HT when enough is available in the synaptic cleft. Serotonin is removed from the synaptic cleft, in a process known as serotonin reuptake, by a selective serotonin transporter (SERT) and taken to a presynaptic neuron, where it is recycled into vesicles, membrane-bound sacs, allowing it to respond more quickly to future signals.
Serotonin-Related Complications
Complications may arise when too much serotonin is present in the body. A well-known complication is serotonin syndrome (SS), or serotonin toxicity (ST), which is when there is an excessive amount of serotonin in the body, likely as a result of an increased medication dosage that is known to elevate serotonin levels (Balaman, O.A. et al, 2023). Patients may experience symptoms within hours of taking medications that cause serotonin syndrome, such as agitation, nausea, high blood pressure, diarrhea, and rapid heartbeat. When it comes to diagnosis, medical professionals focus on the patient’s medical history, especially the types of medications they have been prescribed, tremors, hyperreflexia, which are overactive reflexes, delirium, muscle spasms, uncoordinated movements, and abnormal eye movements. Normally, an individual is diagnosed when they exhibit any 3 of the aforementioned symptoms. In terms of testing for serotonin syndrome, analyses involve the use of CT scans, blood cultures for signs of infection, an electrocardiogram (ECG) to test the heart’s activity, and drug and alcohol screenings, primarily to eliminate other possible causes for experiencing such symptoms. Regarding treatment, patients are kept in a hospital for 24 hours under close observation, or they are prescribed certain medications to combat symptoms they have experienced. For instance, Cyproheptadine blocks further serotonin production, aiding in more stable serotonin levels, and Benzodiazepine medicines reduce muscle stiffness, agitation, and involuntary muscle movements; it seems reasonable to end the ingestion of medications that gave rise to the syndrome (MedlinePlus, n.d.). Once a patient stops taking serotonergic medications, medicines that increase their serotonin levels, they may experience SSRI discontinuation syndrome, where serotonin levels experience a sudden decline; rather than having too much serotonin, there is too little. A prominent sign of this syndrome is “Flu-like” symptoms that arise a few days after the discontinuation of taking these medications, and may last up to 2 weeks; other symptoms include nausea, insomnia, hyperarousal, and imbalance. The prognosis for serotonin syndrome may be life-threatening if not managed properly or quickly; patients may worsen and eventually die.
Serotonin-Related Epilepsy
Serotonin has been found to regulate neuronal excitability, displaying various effects seen in one’s memory, hunger, sleep, mood, movement, feeling for pain, and seizure vulnerability; these serotonin subtypes of G-protein-coupled receptors include 5-HT1A-1F, 5-HT2A-2C, 5-HT3, 5-HT4, 5-HT5A-5C, 5-HT6, and 5-HT7 (Gilliam, F.G., et al., April 1, 2021). GABA and glutamate neurons may be affected by these receptors through hyperpolarization, increasing the cell’s negative membrane potential, or depolarization, lowering the membrane potential’s negative charge; their effects may be seen in seizures. For instance, neurons located within the hippocampus are hyperpolarized by the 5-HT1A receptor, resulting in a more negative neuron membrane. As the negativity increases, it becomes unlikely that the neuron would release an action potential, or an electrical impulse, inhibiting the release of excess glutamate, the excitatory neurotransmitter found to cause seizures. This 5-HT1A receptor appears to have an anticonvulsant effect, preventing increased excitability in the brain and, therefore, seizures. Serotonin is also associated with epilepsy’s common cause of death, SUDEP, the sudden and unexpected death in epilepsy, through respiratory and serotonin dysregulation, or serotonin imbalance. Studies involving mice have demonstrated the importance of serotonin in regulating respiratory drive. When undergoing maximal electroshock-induced seizures (MES), the mice would encounter apnea, or cessation of breathing, before their heart stopped beating. Because seizures can prevent beings from breathing, death can quickly follow if help is not sought out quickly. In cases where there are insufficient amounts of serotonin in the body, the seizure may worsen, and this cessation of breathing is more likely to occur with ease. Further, various studies have shown that many individuals stop breathing after experiencing seizures, with oxygen levels falling below 90% (Gilliam, F.G., et al., April 1, 2021). As seen in the study, about 22% of individuals facing generalized and focal epilepsy suffered from apnea after experiencing a seizure; this can act as an indicator for SUDEP by denying the brain of oxygen. Another study revealed that, after a seizure, the increased presence of serotonin in the body resulted in fewer incidents of postconvulsant or postictal apnea, the cessation of breathing after a seizure (Gilliam, F.G., et al., April 1, 2021). These events could be prevented by boosting serotonin levels through the use of serotonergic medicines, such as fenfluramine, a medication meant to increase serotonin.
Conclusion
Serotonin is a crucial part of the human body, acting as both a neurotransmitter and a hormone, regulating functions such as mood, hunger, sleep, sexual arousal, and digestion. However, too much serotonin can bring about complications, such as serotonin syndrome, and too little serotonin can cause certain disruptions, such as trouble sleeping or depression. It seems to display a complex relationship with epilepsy, as it can either prevent or enable seizures. In preventing seizures, serotonin seems to possess anticonvulsant effects through its constraint on the release of glutamate. Yet, low levels of serotonin can cause a worsened experience with seizures, such as facilitating postconvulsant apnea. It is important to maintain a healthy balance of serotonin, since too much or too little can have negative impacts on the body and the functions it carries out.
References
Serotonin. (2022, March 18). Cleveland Clinic. https://my.clevelandclinic.org/health/articles/22572-serotonin
Bamalan, O. A., & Al Khalili, Y. (2023). Physiology, Serotonin. PubMed; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK545168/
Bakshi, A., & Tadi, P. (2022). Biochemistry, Serotonin. PubMed; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK560856/
National Library of Medicine. (n.d.). Serotonin Syndrome. Medline Plus. https://medlineplus.gov/ency/article/007272.htm
Gilliam, F. G., et al. (2021). Serotonergic therapy in epilepsy. Current opinion in neurology, 34(2), 206–212. https://doi.org/10.1097/WCO.0000000000000901
