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Physiology, Serotonin

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Last Update: March 25, 2021.

Introduction

Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter of an integral physiological role in the human body, it is involved in the regulation of various activities (e.g. behavior, mood, and memory) [1]. In addition, it is utilized as a primary treatment target for many psychiatric and neurological disorders (e.g. major depressive disorder, post-traumatic stress disorder, bulimia nervosa, obsessive-compulsive disorder, anxiety, aggressive behavior, premenstrual dysphoric disorder, panic disorders, social phobia, bipolar disorder, atypical depression, and migraine) [2][3][4]. The use of such treatments in these disorders comes from experimental evidence demonstrating reduced central nervous system (CNS) and plasma serotonin levels [5][6], and significant post-therapeutic outcomes in patients [7][8][9]. However, there is no consensus, as to whether serotonin should be the only factor targeted in these pathologies or there are co-existing factors [10][11].

Cellular

The synthesis of serotonin begins with the essential amino acid tryptophan, which is acted upon by the enzymes tryptophan hydroxylase, and amino acid decarboxylase. Although, it was thought to be mainly in the CNS raphe nuclei maintaining cortical functions, it is also found in other systems such as enterochromaffin cells (gastrointestinal), platelets (coagulation), where it regulates tone, functionality, and blood supply [12][13][14].

The release of 5-HT in the synaptic cleft, where it has a receptor-dependent effect, will cause adrenergic-like responses (e.g. mydriasis, increased heart, and respiratory rates, etc.). However, different serotonergic and adrenergic receptor subtypes might show distinctive molecular affinities and actions [15].

In the post-synaptic membrane, metabotropic G-protein receptors with high 5-HT affinity initiate second messenger cascades. The cascades' visceral effect differs based on the receptor subtype. The metabotropic receptors (HTR1/2), alongside its different subtypes, decreases cyclic-AMP (CAMP) through the coupling of Gi/o protein alpha subunit (GNAI) in which the activity of adenylate cyclase (ADCY) will be inhibited [16]. On the other hand, (HTR4/6/7) cascades work by coupling of Gs protein alpha (GNAS), which stimulates ADCY, leading to increased CAMP [17]. The ionotropic receptors (HTR3) maintain electrolytic gradients [18]. The electrolyte gradient difference between sodium influx and potassium efflux will depolarize the membrane [19][20].

Moreover, as 5-HT plays a role in increasing CAMP concentration, a partial function is the downregulation of the innate immune system [21][22]. This plays a role in symptomatic control in some hypersensitive pathologies such as asthma [23][24].

Organ Systems Involved

Serotonin has a multiorgan, physiological mechanisms utilizing it, these include:

  • Coagulation, particularly patients on an anticoagulant (e.g., warfarin) [25]
  • Cardiac arrhythmia, as 5-HT will increase myocyte intracellular calcium, which increases contractility rate, leading to arrhythmias (e.g., atrial fibrillation, ventricular tachycardia) [26][27].
  • Neurological disorders, as 5-HT is a major pathophysiological factor in epilepsy [28][29][30], and many neuropsychiatric disorders as discussed above.
  • Hypertensive patients, as serotonin's vasoconstricting action leads to disrupted feedback and regulation of blood pressure, which causes fluctuations in blood pressure [14][31][32].
  • Endocrine and metabolic processes, as increasing serotonin causes a decrease in bone mineral density and abnormal regulation of metabolic processes such as lipolysis and gluconeogenesis [33][34][35].
  • Patients with ocular disorders (e.g., glaucoma) [36][37][38].

Function

There are varied drugs that affect the serotonergic system in the CNS and peripherally:

5-HT Receptors Agonist/Partial Agonist (e.g., zolmitriptan)

  • There are varied post-synaptic 5-HT receptors, which, when activated, may cause an excitatory or inhibitory effect on the post-synaptic cell. Therefore, maximizing the receptor's functionality in serotonin-deficient disorders will optimize the function of the systems requiring this neurotransmitter [39][40][41].

Selective Serotonin Reuptake Inhibitors (SSRI) (e.g., fluoxetine) 

  • Predominantly used in neuropsychiatric disorders, SSRIs work by blocking the major 5-HT down-regulating pre-synaptic reuptake channels (e.g., SLC6A4), resulting in an increase in 5-HT concentration. This consequently resets the abnormal feedback loop of the patient [42][20].

Monoaminoxidase Inhibitors (MAOI) (e.g., selegiline)

  • Monoaminoxidase is one of the enzymes that degrade 5-HT. The reversible or irreversible inhibition of such enzymes will result in less degradation of 5-HT and other adrenergic neurotransmitters within the synaptic cleft (e.g., norepinephrine) [43].

Tricyclic Anti-depressant (TCA) (e.g., imipramine)

  • Pre-synaptically, it blocks 5-HT and norepinephrine reuptake channels. Post-synaptically, it blocks cholinergic and histamine receptors. As a result, the concentration of 5-HT is increased [44].

Similarly, there is also a range of illegal drug groups (e.g., ecstasy) that will elevate 5-HT concentration.

Pathophysiology

Serotonin syndrome (SS) or toxicity (ST) is a combination of hyper-serotonergic stimulation on CNS and visceral organs. Toxicity can present when a patient receives a combination of 5-HT elevating drugs or an overdose [45][46]. The spectrum of clinical manifestations can be life-threatening; thus, recognition of the manageable signs and symptoms that appear first is crucial to prevent deterioration. The signs and symptoms may develop 24-hours after administration, as the drug's pharmacokinetic and pharmacodynamic processes take place. The diagnostic mechanism of SS is mostly dependent on a thorough history and physical examination while considering Sternbach, Radomski, and Hunter's criteria for diagnosis [46].

The predominant diagnostic mechanism is considering the presentation dependent on three parts, which are the neuromuscular, autonomic, and mental manifestations of serotonin toxicity [47][48][49][50]:

Neuromuscular

  • Tremor
  • Hyperreflexia
  • Myoclonus
  • Babinski sign
  • hypertonia

Autonomic

  • Mydriasis
  • Diaphoresis
  • Tachycardia
  • Tachypnea
  • Hyperthermia
  • Vomiting
  • Arrhythmias

Neurological

  • Agitation
  • Excitement
  • Insomnia
  • Confusion
  • Anxiety

Clinical Significance

Drugs that elevate or deplete 5-HT concentration peripherally or centrally need to be dosed appropriately and in a patient-oriented manner. Dose titration following initiation of therapy and monitoring patient symptoms is of therapeutic benefit [51][52].

The goal of therapy is to maintain serum serotonin level (SSL) at a range between 101 to 283 nanograms per milliliter (ng/mL). Clinically, frequent checks of vital signs, cardiac rhythm, blood analysis, and regular review of signs of toxicity or minor side effects are prudent, given the risk of toxicity [53][46], and particularly if the serotonergic drug has recently been commenced. Conversely, if the patient's hypo-serotonergic symptoms have not improved, a dose increase may be required. Additionally, tryptophan plasma levels have been demonstrated as a significant indicator of decreased or increased SSL and its concentration centrally [54][55].

Most patients take serotonergic drugs orally as a pill preparation. Alternative methods include dermal patches, nasally, intramuscularly (IM), and intravenously (IV). It is important to note that each route has a different half-life, efficacy, and potency of the type of drug administered. Furthermore, in IV administration, one must be careful and monitor blood pressure alongside other vital signs and cardiac activity to prevent sudden deterioration [56][57]. Also, IM injections applied for local vasoconstricting effects cause pain [58]. Intraperitoneal (IP) administration is used in experimental research in mice and has shown a correlation with disrupting thyroid hormone function [59][60][59].

Treatment of serotonin toxicity is mainly dependent on decreasing the dose of the offending serotonergic agonist(s) taken by the patient. The maintenance of the patient's vital signs, continuous cardiac monitoring, and sedation by benzodiazepines are required; moreover, controlling the patient's hyperthermia by IV cold fluid and antipyretics is essential to prevent further autonomic and neuromuscular disruption [61][62]. Eventually, a serotonin antagonist might be necessary. Cyproheptadine is the first-line choice and is considered an antidote, though caution is advisable as there are reports of prolonged sedation and transient hypotension [63]. The resolution of mild to moderate cases can be within 24 hours, and early recognition and management are key to improved prognosis [64].

Review Questions

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