Serotonin: Distribution, Synthesis and Metabolism

Introduction to Serotonin

• 5-Hydroxytryptamine (5-HT) is also known as serotonin.
• Serotonin has a wide tissue distribution and a variety of pharmacological actions.

Serotonin Distribution and Synthesis

• Serotonin is found in plants such as pineapples, bananas, tomatoes, and nuts.
• It is primarily found in the brain, gastrointestinal tract, and blood platelets.
• 5-HT is metabolically degraded upon entering circulation.
• Serotonin is stored in granules in the CNS and GI tract.
• Serotonin is metabolized by monoamine oxidase after release.

Serotonin Biosynthesis and Metabolism

• Serotonin is synthesized in two key steps.
• Tryptophan hydroxylase converts tryptophan into 5-hydroxytryptophan (5-HTP) in the first step.
• Aromatic L-amino acid decarboxylase converts 5-HTP into serotonin in the second step.
• Serotonin is metabolized primarily by the enzyme monoamine oxidase (MAO), producing 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in urine.

Melatonin Pharmacology

• Melatonin is N-acetyl-5-methoxytryptamine, a simple methoxylated and N-acetylated product of serotonin.
• It is produced and released primarily at night.
• Melatonin is suspected of playing a role in the sleep-wake behavior of humans.
• Melatonin is promoted commercially as a sleep aid by the food supplement industry.
• Literature supports the use of melatonin in ameliorating jet lag.
• Melatonin is used in oral doses of 0.5-5 mg, usually administered at the destination bedtime.

Serotonin (5-HT) Physiological Actions

• Serotonin plays a physiologic role as a neurotransmitter in both the CNS and the enteric nervous system.
• It may have a role as a local hormone that modulates gastrointestinal activity.
• Brain serotonergic neurons are involved in numerous diffuse functions such as mood, sleep, appetite, temperature regulation, perception of pain, and regulation of blood pressure and vomiting.
• Serotonin also appears to be involved in clinical conditions such as depression, anxiety, and migraine.

Pharmacological Significance - Nervous System

• 5-HT (Serotonin) is a chemical transmitter in the nervous system of vertebrates and many invertebrates.
• Serotonin is released by tryptaminergic neurons distributed in the brain.
• It plays a critical role in regulating mood, behavior, and various physiological functions.
• Disruptions in 5-HT function may lead to sleep disorders, appetite disturbances, mood disorders, sexual dysfunction, motor activity issues, and migraine.

Pharmacological Significance - Sleep and Behavior

• 5-HT controls the sleep-wakefulness cycle.
• Depletion of 5-HT causes insomnia, which can be reversed by 5-hydroxytryptophan.
• Disturbances in brain 5-HT metabolism are suspected as a cause of certain psychiatric disorders.
• 5-HT3 receptors in brain limbic and cortical areas are known to be involved in controlling mood, emotion, reward, and memory.

Pharmacological Significance - Emesis

• Antiemetic activity has been generally associated with dopamine antagonist drugs.
• Studies indicate that selective 5-HT3 receptor antagonists can prevent emesis associated with anti-cancer drugs and radiotherapy.

Pharmacological Significance - Gastrointestinal and Cardiovascular Systems

• 5-HT is believed to act as a local hormone for the initiation and sustenance of intestinal peristalsis.
• Serotonin reduces the volume, acidity, and pepsin content of the gastric juice and promotes the production of mucus.
• 5-HT constricts the renal, pulmonary, and cerebral blood vessels.
• Serotonin has some positive inotropic and chronotropic action on the heart.

Pharmacological Significance - Platelets and Hormone Secretion

• Platelets do not synthesize 5-HT but take it up from the circulation and store it.
• 5-HT release, following a vascular injury, along with other mediators of injury, activates platelets, which then promote vascular occlusion and vasoconstriction.
• Tryptaminergic mechanisms are involved in the control of the release of certain hormones.
• Sex hormones may affect mood and the mental state by activating the central 5-HT receptors.

Serotonin (5-HT) Receptors Overview

• 5-HT receptors include 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 subtypes.
• These receptors are coupled to various intracellular signaling pathways like Gi/o, Gq, and Gs.
• Some receptors affect cyclic AMP levels, Ca2+ levels, and PKC activation.
• They can be inhibitory, stimulatory, or cause depolarization.

Serotonin Agonists - Mechanism

• Serotonin agonists are drugs that activate serotonin receptors, mimicking the neurotransmitter's effects.
• They work by binding to specific serotonin receptor subtypes, either enhancing or modifying neurotransmission.

Serotonin Agonists - Classification

• Direct agonists bind directly to serotonin receptors (e.g., sumatriptan).
• Indirect agonists increase serotonin levels by inhibiting reuptake or degradation (e.g., SSRIs).

SSRIs Examples

• Citalopram
• Escitalopram
• Fluoxetine
• Fluvoxamine
• Paroxetine
• Sertraline

Common Serotonin Agonists and Their Uses

• Triptans (e.g., sumatriptan, rizatriptan) are 5-HT1B/1D receptor agonists that constrict cranial blood vessels and inhibit inflammatory neuropeptides, reducing migraine pain.
• Buspirone, a 5-HT1A receptor agonist, is used for generalized anxiety disorder (GAD).
• Buspirone does not cause sedation or dependence like benzodiazepines.
• Lorcaserin (5-HT2C agonist) influences hypothalamic satiety centers, promoting weight loss for appetite suppression.

Serotonin Antagonists - Mechanism and Classification

• Serotonin antagonists block serotonin receptors, preventing serotonin activity.
• These drugs are used to counteract excessive serotonin effects, such as nausea, psychosis, and serotonin syndrome.
• Selective receptor blockers target specific serotonin receptors (e.g., ondansetron for 5-HT3).
• Broad-spectrum antagonists affect multiple serotonin receptor subtypes (e.g., atypical antipsychotics).

Common Serotonin Antagonists and Their Uses

• Ondansetron is a 5-HT3 antagonist used to prevent chemotherapy-induced nausea and vomiting by blocking serotonin signals in the gut and brain.
• Cyproheptadine is a 5-HT2 antagonist used to treat serotonin syndrome by counteracting excessive serotonin activity.

Atypical Antipsychotics

• Atypical antipsychotics like risperidone, olanzapine, and clozapine block 5-HT2A receptors along with dopamine receptors.
• They help treat schizophrenia, bipolar disorder, and depression.

5-HT6 and 5-HT7 Antagonists

• 5-HT6 Antagonists (Idalopirdine, SB-742457) are under investigation for Alzheimer's disease and cognitive enhancement.
• 5-HT7 Antagonists may offer antidepressant and anxiolytic benefits.