Serotonin Structure, Function, Physiology, and Dysfunction
Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter in the brain and spinal cord has a significant influence on virtually all aspects of physiological, behavioral, and cognitive function, and as a consequence dysregulation of this signaling system contributes significantly to myriad neurological and psychiatric disorders. Serotonin influences psychological activity such as mood, reward, memory, anger, appetite, affection, perception, cognition, and sexuality. Most emotions and behaviors in humans are regulated by serotonin. Due to its modulation of various neural activities related to mood, serotonin is often labeled the ‘happy hormone’ or ‘feel-good hormone’.
Serotoninergic neurons in the central nervous system (CNS) modulate the activity of brain circuits and project to the limbic, midbrain, cortical, hindbrain regions, and spinal cord.
Peripherally, serotonin also regulates several biological processes such as platelet aggregation. Serving as a paracrine messenger, a hormone acting on cells in the vicinity, serotonin is secreted by the digestive system influencing gut motility, and in keeping with this a relatively small population of neurons in the CNS produce serotonin with the majority (~ 95%) found outside the CNS in the gut periphery.
Synthesis and Metabolism
Serotonin and its precursor, the essential amino acid L-tryptophan are aromatic compounds comprised of a five ring NH containing indole group fused to a benzene ring (Figure 1). The rate limiting enzyme L-tryptophan hydroxylase (TPH) converts L-tryptophan to 5-hydroxytryptophan (5-HTP) in a reaction similar to the limiting action of tyrosine hydroxylase in catecholamine synthesis. The aromatic amino acid decarboxylase, 5-hydroxytryptophan decarboxylase subsequently decarboxylates 5-HTP to generate serotonin (5-HT) in a reaction reminiscent of a mechanism also deployed in catecholamine biosynthesis. Inhibitors of tryptophan hydroxylase are used clinically to treat disorders related to abnormal serotonin levels, and there are two isoforms - TPH1 found in the periphery and TPH2 in the brain, and these enzymes provide attractive targets for selective drug development.
Serotonin is metabolized by the central and peripheral enzyme, monoamine oxidase (MAO) principally MAO-A, that reside on the outer mitochondrial membrane in the cell. The oxidative deamination of serotonin by MAO produces an intermediate, 5-hydroxyindole acetaldehyde, which is further processed by aldehyde dehydrogenase to generate the major serotonergic metabolite, 5-hydroxyindole acetic acid (5-HIAA). The normal excretion of 5-HIAA in the urine as a product of serotonin metabolism is 2 to 8 mg/24 hours.
Considering the role of serotonin in depression and other affective disorders, inhibition of MAO’s is a key mechanism for treatment as it limits the metabolism of the monoamine, thereby increasing its availability. The serotonergic system serves as a target for majority of antidepressant and anxiolytic agents used in treatment to alleviate symptoms of dysfunction.
The characterization of serotonin receptors has benefited greatly from the development of selective and potent agonists and antagonists. There are known to be 15 subtypes of serotonin receptors encoded by separate genes and are grouped into 7 families 5-HT1 to 5-HT7 based on their analogous function and pharmacological profile, i.e., response to select agonists and antagonists.
Serotonin, like other monoamines, exerts its effects through G protein-coupled receptors with the exception of 5-HT3, which is a serotonin-gated ion channel. The receptors have a wide distribution in the brain and gut of humans and other mammals. It is important to note that the receptors in different species differ to some degree in their distribution and pharmacological properties which should be kept in mind when interpreting the literature.
Serotoninergic receptors are located in all regions of the brain underpinning serotonin’s role in all aspects of physiological, behavioral, and mental functioning. Serotonin axons project to the frontal, temporal, parietal cingulate, insular cortices, hippocampal formation, amygdala, striatum, substantia nigra, and hypothalamus in the brain and to all segments of the spinal cord. Some regions are more densely innervated than others with certain receptor subtypes more highly enriched in certain regions. The serotonin circuits leverage these receptors at different sites in the brain to maintain normal function and homeostasis.
Majority of serotonin receptors subtypes are present at post-synaptic sites and have been characterized pharmacologically and by advanced imaging and molecular techniques. Serotonin signaling is under inhibitory control from 5-HT1A somatodendritic autoreceptors in the raphe, and 5-HT1B and 5-HT1D autoreceptors at serotonergic terminals at target sites in the brain. The self-inhibition of the serotonin system via these autoreceptors is a key mechanism optimizing neurotransmission and is key for optimal function and homeostasis.
Sustained activation of serotonin receptors results in functional and physical alterations, and changes in neurotransmission resulting from receptor disinhibition, internalization, or recycling to the membrane. Once released into the extracellular space serotonin participates in classic neurotransmission, traversing the synaptic cleft to bind to post-synaptic receptors on target cell. Serotonin also participates in volume transmission, diffusing to act on extra-synaptic sites further away. It is rapidly cleared from the extracellular space in an ATP-dependent manner by the Na+/Cl-- dependent serotonin transporter, SERT. The reuptake by SERT regulates the levels of extracellular serotonin, and antidepressants selectively block the activity of the transporter to maintain therapeutic levels of the serotonin. Following reuptake serotonin can be metabolized by monoamine oxidase, or conversely repackaged in vesicles by the carrier protein, vesicular monoamine transporter 2 (VMAT2).
Evidence links dysfunction of the serotonergic system and its receptors to anxiety, depression, obsessive-compulsive disorder (OCD), migraines, pain, nausea, and conditions such as obesity, anorexia-bulimia, panic disorders, and drug abuse. The system is also implicated in dementia, neurodegenerative disorders, Schizophrenia, Alzheimer’s, and Parkinson’s Disease.
Therapeutic agents that target this system have been leveraged in the treatment of serotonin implicated disorders. Antidepressants of the class selective serotonin reuptake inhibitors (SSRIs), like fluoxetine, inhibit the reuptake of serotonin by the transporters, consequently elevating serotonin levels and ameliorating the symptoms of depression and OCD. Another class of antidepressant’s, MAOI’s inhibit the catalytic activity of monoamine oxidase and function to raise the levels of serotonin and other biogenic amines. This line of MAOI treatment is used with caution due to severe side effects related to Serotonin syndrome caused by serotonin toxicity. Agonists of the 5-HT1A receptors, such as buspirone, (an anxiolytic agent) are deployed in the treatment of anxiety; 5-HT1D and 1F agonist sumatriptan is effective in the treatment of migraines; agonists have also been used in the treatment of Schizophrenia; antagonists of the ligand-gated ion channel 5-HT3 receptor, like ondansetron relieve nausea. It has long been established that central 5-HT2A or 2C serotonin receptors mediate the hallucinations induced by the psychoactive drug lysergic acid diethylamide (LSD).
Serotonin Anatomy and Pathways
Organization of the serotonin system is similar across species, and serotonin synthesizing cells are confined to the rostrocaudal length of the midline raphe nucleus in the brainstem. This localization was described as early as the 1960’s.
Lateral to the raphe, the reticular formation also contains these aminergic neurons. Serotonergic neurons display meager myelination and project to all regions of the nervous system underscoring their diverse role in physiological, behavioral and cognitive function.
Imaging and molecular techniques depict a continuum of two distinct subpopulations of neurons, divided into a rostral group and a caudal group.
Raphe Rostral Group
The rostral group which comprises 85% of the serotonergic neurons originates in the mesencephalon and rostral pons and extends axons to the forebrain and other areas of the brain.
This group contains 4 nuclei, namely the caudal linear, dorsal raphe (DRN), median raphe (MRN), and interpeduncular. The axons emerge from these nuclei and branch into a lateral projection that travels in the internal capsule to innervate the cortex, and a longitudinal projection that traverses the medial forebrain bundle to the hypothalamus, basal forebrain, septum, basal ganglia, and amygdala, and proceeds through the cingulum to project to the hippocampus and medial cortex. The serotonin neurons in the rostral group colocalize other catecholamine and peptides, with a larger majority colocalizing Substance P. Cortical serotonergic innervation overwhelmingly arises from the DRN, and these neurons have small, widely spaced varicosities and participate in volume transmission. These neurons are especially vulnerable to damage by amphetamine derivatives like ecstasy. In contrast the axon’s of the MRN that project to the frontal cortex and hippocampus elaborate larger, tightly spaced varicosities that form archetypal, classic synapses. Afferents to the nuclei of the rostral raphe group emanate from the forebrain limbic areas, and it receives glutamatergic input from the hypothalamus, cingulate cortex, and ventral tegmental area. Additionally, the hypothalamus provides GABAergic inputs.
Raphe Caudal Group
That caudal group contributes the remaining 15% of serotonergic neurons of the raphe and is made up of raphe magnus, raphe obscurus, raphe pallidus - the smallest of the raphe nuclei, and ventral medullary reticular formation.
The caudal group projects to the visceral and somatic motor nuclei, including cranial motor, trigeminal, facial, hypoglossal located in the lateral reticular formation of the brainstem, and it also has descending efferent projections to all segments of the spinal cord. It receives afferents from the hypothalamus, periaqueductal gray, amygdala, bed nucleus of the stria terminalis, medullary reticular formation, supplemented by visceral sensory inputs.
The serotonergic circuitry in the brain and spinal cord is wide-ranging and as a consequence it plays a complex and dynamic role in the nervous system. It is implicated in mood, emotion, cognition, learning and memory, motor behavior, circadian rhythm, appetite, sexuality, aggression, and autonomic functions, amongst others.
Serotonin exerts its effect directly or may play a more modulatory role in synchronizing the response and activity level with the level of arousal. Evidence supports serotonin's involvement in behavioral arousal and activity. The DRN and other raphe neurons have have been shown to have a regular firing pattern during waking that starts to decline with sleep and to be almost completely abolished during REM sleep.
Serotonin is documented to modulate gross motor activity and, furthermore, there is enhanced activation of a group of serotonergic neurons observed with motor function that is related to the repetitive central pattern generator. The activity of these subset of neurons is not perturbed by stressful situations that invoke the sympathetic nervous system. The association of serotonin with both types of activity - tonic and repetitive-, suggests an integrative role of serotonin in facilitating motor activity in response to the circumstance in question in coordination with other physiological, neuroendocrine, and autonomic functions. This is accompanied with the concomitant inhibition of sensory processing of inputs unrelated to the situation, allowing for a focused motor response.
Serotonin regulation of the circadian rhythm is mediated by the innervation from the median raphe to the hypothalamic suprachiasmatic nucleus (SCN). The SCN functions as an endogenous pacemaker, maintaining a 24h rhythm which can be entrained to the diurnal light-dark cycle. This internal clock is critical for choreographing timings of various behavioral and physiological functions, including the activity and cellular processes in different parts of the brain and other tissue that successfully work together and generate an overt rhythm, essential for proper function. Serotonin and its agonists exhibit an inhibitory effect on the SCN biological clock by diminishing the nucleus's excitatory response to light. Considering its modulation of the SCN, serotonin afferents may be involved with the disruption of circadian rhythms in serotonin-related affective disorders.
Serotonin has been studied extensively for its impact on the releasing and inhibitory factors secreted by the hypothalamus, like corticotrophin-releasing hormone (CRH) that influence the release of hormones, such as adrenocorticotrophic hormone (ACTH) from the anterior pituitary gland. Administration of drugs that manipulate the serotonergic system alter the levels of different hormones. The endocrine response is a good indicator of central serotonergic function and may be used in clinical settings to assess the effect of serotonergic agents employed for treatment of various disorders in psychiatry.
In pain management serotonin has a dual role as a facilitator in the periphery, and conversely as a facilitator and inhibitor in the dorsal horn of the spinal cord and the central pain descending pathway. Its effect is very much dependent on the distribution of receptor subtypes, locus of pain, and where the neurotransmitter acts. The peripheral excitation of primary nociceptive nerve fibers by serotonin leads to inflammation and the perception of pain, and this mechanism is also involved in the etiology of peripheral neuropathy. Centrally the bidirectional role of serotonin is determined by the the receptor subtype at the site of action. Fibers from the raphe, including the nucleus raphe magnus form a portion of the descending pathway that projects to the dorsal horn of the spinal cord - a site that receives the first central relay of pain signals from the periphery. Serotonin serves to inhibit the incoming pain signals from the periphery. Due to the conflicting role of serotonin in pain, leveraging the noradrenergic system - as evidenced by the effectiveness of selective serotonin/norepinephrine reuptake inhibitors (SNRIs) - is more suited to the management of pain. In addition, painful disorders such as irritable bowel syndrome, fibromyalgia, migraine and other headaches have a clear connection with the serotonergic system.
Alteration is serotonin levels affects mood, a cardinal symptom of depression. The monoamine hypotheses of depression postulated the underlying paucity of neurotransmitters serotonin and noradrenaline and the amelioration of symptoms by therapeutic agents that raised the levels of these monoamines as proof of concept for their involvement. SSRIs and SNRIs are widely prescribed as a first line of treatment for depression, with varying degrees of effectiveness. The influence of dietary tryptophan on mood and cognition further suggests a role of serotonin in the etiology of depression and for memory and learning.
Serotonin is most commonly associated with mental disorders. Various studies using single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have revealed that serotonin affects anxiety, mood, depression, addiction, and autism disorders.
Lower levels of serotonin is a central postulate of the serotonin hypothesis of depression. In clinical settings serotonin function is often associated with depression. PET scans deployed to gauge serotonin function, reveal depleted levels of the serotonin precursor tryptophan in depressed patients. Another line of evidence in support of the serotonin hypothesis of depression shows the pathophysiology of depression involves the alterations of neurons and glia in the prefrontal cortex and hippocampus at sites including those that receive strong serotonergic innervation.. PET studies have further demonstrated the upregulation of 5-HT1A autoreceptors in the raphe of depressed individuals and a predisposition for depression with higher levels of this receptor. The utility of SSRIs and SNRIs that increase the levels of monoamines is a cornerstone in treatment of depressive disorders.
Major depressive disorder is closely related to the low availability of the serotonin transporter, SERT, in the midbrain. A neuroimaging study found lowered levels of SERT binding sites in depressed people reflecting potentially a compensatory reduction of serotonin reuptake to ameliorate serotonergic activity.
Increasingly serotonergic agonists and antagonists are being used therapeutically, and it is important to be alert to Serotonin syndrome, a severe condition which can occur within 24 hours of the initiation, alteration, and overdose of serotonin or certain serotoninergic agents. This symptoms of this disorder include tachycardia, agitation, hyperreflexia, confusion, and can be prevented by serotonin antagonists such as cyproheptadine.
Anxiety and affective disorders are improved with the administration of SSRIs. Verbal motivation and expectancies of improvement influence treatment outcome through their effect on brain monoamine transporters, evidenced as a 'placebo effect'. SSRIs may contribute to the alterations in dopamine neurotransmission in subject with social anxiety disorder (SAD). A PET study indicated the dopamine transporter contributed more significantly to reducing social anxiety symptoms of the subjects compared to the serotonin transporter. This suggests that the therapeutic response to SSRIs has less to do with the serotonin transporter and more with the dopamine 'reward' circuit invoked by expectancies, and an enhanced interaction of the serotonin and dopamine system in concert with the pharmacologic inhibition of the serotonin transporter.
Changes in serotonergic activity are also correlated with other mental disorders such as bipolar disorder. Using SPECT, researchers have been successful at assessing the degree of decreased availability of the serotonin transporter, which is assumed to be a biomarker of the severity of the bipolar disorder. Elevated binding sites for the serotonin transporter in the cortex, thalamus, and striatum are observed with reduced binding in the raphe of bipolar disorder patients. The increased presence of the transporter at cortical sites could account for the anxiety noted in bipolar disorder. The serotonergic system also influences addiction. A SPECT study of opioid-dependent patients treated with low-dose methadone showed lower serotonin transporter availability compared to the control group. A study on autism employing a similar paradigm using SPECT imaging showed that levels of serotonin transporter were much lower in parts of the medial frontal cortex in children with autism. In adults with autism, decreased levels of the serotonin transporter occur in the anterior or posterior cingulate cortex.
Serotonin in the Periphery
In addition to the CNS, serotonin is also released from the gastrointestinal tract and platelets. Serotonin is mostly synthesized in the intestinal mucosa, more precisely by the enterochromaffin cells that line the gastrointestinal tract and account for ~95% of the total serotonin produced in the body. These cells, important for gut function, operate as 'mechnosensors' and 'chemosensors' that transduce mechanical inputs such as peristaltic activity, or chemical signals associated with dietary sources, gut microbiota or luminal pH into a biochemical signals that results in serotonin secretion. Serotonin stimulates intestinal reflexes, including gut contractility. Serotonin synthesized from enterochromaffin cells is carried and stored in platelets via serotonin reuptake transporters. As a result, serotonin plays a role in thrombosis, hemostasis, and immunity. Serotonin levels in the blood increase due to platelet activation in response to inflammation.
The cardiovascular system is differentially influenced by serotonin owing to the different effects mediated by receptor subtypes and transporters. It elicits opposing responses comprising of vasodilation and constriction, bradycardia or tachycardia, blood pressure elevation or depression (hypertension or hypotension). Serotonin controls hemostasis and platelet function through resistance and blood pressure control mechanisms. This is related to the vasodilation and vasoconstriction in smooth muscle tissue and blood vessel walls. Furthermore, cardiac function is regulated by serotonin through electrical conduction and closure of heart valves. This monoamine modulates cardiac function evidenced by serotonin producing carcinoid tumors in patients with cardiac disorders. Excess serotonin levels in this condition trigger atrial fibrillation, mediated by serotonin binding to 5-HT4 receptors.
Recent studies indicate that the platelet activation system is influenced by intracellular serotonin activity. Serotonin promotes platelet aggregation and vasoconstriction of blood vessels peripherally at sites of injury. The 'serotonylation' catalyzed by enzyme transglutaminase, covalently links serotonin with small G proteins to stimulates platelet aggregation. The activity of this subset of platelets is influenced by covalent binding to clotting factors and adhesion proteins on the surface of platelet cells.
Serotonin drives excitation of the brainstem respiratory network. A plethora of evidence links different serotonin receptor subtypes with respiratory function. For maintaining intrinsic respiratory rhythms, the binding of serotonin to 5-HT4 receptors in the brainstem pre-Bötzinger complex is essential. Activation of 5-HT2A receptors in the respiratory network is also responsible for the integrity of the respiratory rhythm. Hypoxia induces increased secretion of serotonin in pulmonary oxygen sensing cell that could putatively be responsible for activation of serotonin receptors located on vagal afferents. Hypoxia in patients with pulmonary artery hypertension increases serotonin production.
During the current pandemic, SSRIs have also been associated with a lower risk of death in COVID-19-positive patients. A retrospective study examined the role of the SSRI in reducing the risk of death in COVID-19 patients. The results indicate a reduced relative risk in patients given fluoxetine or fluvoxamine compared to the control group not prescribed SSRIs. These findings are supported by a randomized clinical study showing fluvoxamine reduced clinical symptoms in COVID-19 patients for 15 days compared with the placebo group. In this capacity SSRIs function by contracting the inflammatory response, however this utility of SSRIs in the treatment of COVID-19 needs further evaluation.
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