5-HT (5-Hydroxytryptamine) (Serotonin)

• Serotonin (5-Hydroxytryptamine or 5-HT) is a monoamine neurotransmitter derived from the amino acid tryptophan.
• 5-HT (5-Hydroxytryptamine) (Serotonin) influences a wide range of physiological and behavioral processes.

Synthesis:

• From the amino acid tryptophan by tryptophan hydroxylase and subsequent decarboxylation.

Storage:

• High concentration in enterochromaffin cells in the gut, platelets, and in the CNS as a neurotransmitter.

Metabolism:

• Primarily by monoamine oxidase (MAO).

Functions of 5-HT:

• Central Nervous System: Regulates mood, appetite, sleep, and cognition.
• Gastrointestinal Tract: Controls intestinal movements and secretion.
• Vascular System: Modulates vascular tone and platelet aggregation.

Pharmacological Effects of Serotonin

Here is a concise summary of those (actually histamine) effects:

• Vasodilation of small vessels → lowers blood pressure
• Increased capillary permeability → leads to edema and urticaria
• Smooth muscle contraction (via H1) → causes bronchoconstriction
• Stimulation of gastric acid secretion (via H2)

5-HT Receptors:

Serotonin acts through at least 14 different receptor subtypes, grouped into seven families (5-HT1 to 5-HT7). These receptors are involved in diverse physiological responses.

1. 5-HT1 Receptors:

   • Subtypes: 5-HT1A, 1B, 1D, etc.
   • Functions: Inhibit adenylate cyclase activity, involved in vasoconstriction and neurotransmission.

2. 5-HT2 Receptors:

   • Subtypes: 5-HT2A, 2B, 2C.
   • Functions: Mediate smooth muscle contraction, platelet aggregation, and various CNS effects.

3. 5-HT3 Receptors:

   • Function: Ion channel receptors involved in emesis (vomiting) and neurotransmission.

4. 5-HT4 to 5-HT7 Receptors:

   • Functions: Diverse roles including modulation of neurotransmission, cardiac function, and circadian rhythms.

5-HT Antagonists

1. 5-HT3 Antagonists:

   • Purpose: Mainly used as antiemetics to prevent nausea and vomiting associated with chemotherapy, radiation therapy, and surgery.
   • Examples: Ondansetron, granisetron, palonosetron.
   • Mechanism: Block 5-HT3 receptors in the central nervous system and gastrointestinal tract to inhibit the vomiting reflex.

2. 5-HT2 Antagonists:

   • Purpose: Used in the treatment of schizophrenia, depression, and migraine.
   • Examples: Olanzapine, risperidone (antipsychotics), cyproheptadine (antihistamine with 5-HT2 antagonism).
   • Mechanism: Block 5-HT2 receptors to modulate neurotransmission involved in mood and perception.

3. Other 5-HT Receptor Antagonists:

   • Purpose: Various applications depending on the specific receptor subtype targeted.
   • Examples: Trazodone (5-HT2 antagonism for depression and insomnia), pizotifen (migraine prophylaxis).

Below is a concise table summarizing selected serotonin (5-HT) receptor

Receptor	Location	Signaling Pathway	Pharmacological Actions	Example Agonist	Example Antagonist
5-HT1B/1D	Cerebral blood vessels, presynaptic nerves	Gi → ↓ cAMP	– Causes vasoconstriction in intracranial blood vessels – Inhibits nociceptive (pain) transmission	Sumatriptan (for migraine)	(No common clinical antagonist)
5-HT2A	Smooth muscle, platelets, CNS	Gq → ↑ IP3, DAG	– Vasoconstriction or vasodilation depending on location – Platelet aggregation – CNS effects (mood, perception)	(Not typically used clinically)	Ketanserin (experimental), Risperidone (antipsychotic)
5-HT2B	Heart (valves), stomach fundus	Gq → ↑ IP3, DAG	– Involved in cardiac valve fibrosis (when overstimulated) – Smooth muscle contraction in GI tract	(Not typically used clinically)	(No major selective antagonist)
5-HT2C	CNS (choroid plexus, hypothalamus)	Gq → ↑ IP3, DAG	– Appetite suppression – Mood regulation	Lorcaserin (for weight loss)	(No major selective antagonist)
5-HT3	Chemoreceptor trigger zone (CTZ), GI tract	Ligand-gated ion channel	– Emesis (vomiting reflex) – GI motility and secretion	(Not used clinically as agonist)	Ondansetron, Granisetron (antiemetics)
5-HT4	GI tract, CNS	Gs → ↑ cAMP	– Enhanced GI motility – Some CNS effects	Metoclopramide, Cisapride (prokinetic)	(No major selective antagonist)

Notes:

• 5-HT1 receptors (1B/1D) are key targets for migraine therapy (triptans).
• 5-HT2 receptors have diverse roles in the cardiovascular system, smooth muscle, and CNS. Antipsychotics often block 5-HT2A receptors.
• 5-HT3 is an ionotropic receptor crucial in the vomiting reflex. Antagonists like ondansetron are widely used to manage chemotherapy-induced nausea.
• 5-HT4 agonists are used as prokinetic agents to enhance GI motility.

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