07 Serotonin Flashcards
What essential amino acid is serotonin synthesized from?
Tryptophan
The rate-limiting enzyme in serotonin synthesis is?
Tryptophan Hydroxylase
Is tryptophan hydroxylase rate-limiting in synthesis of serotonin in CNS?
Not rate-limiting because of low tryptophan levels
What co-factors are required for serotonin synthesis?
O2 and reduced pteridine cofactor
What enzyme is involved in synthesis of catecholamines like serotonin?
L-aromatic amino acid decarboxylase
Uses pyridoxine cofactor
What is serotonin converted into in the pineal gland?
Melatonin
How is serotonin metabolized?
Neuronal action terminated primarily by high affinity active reuptake mechanism (SERT) and then intraneuronal conversion by monoamine oxidase (MAO) and aldehyde dehydrogenase to 5- hydroxyindole acetic acid
Where is the majority of serotonin distributed?
90%– Enterochromaffin cells of GI mucosa
- synthesis and storage
- slow spontaneous release (1 day)
Of the locations serotonin is distributed, where is it not synthesized?
Blood platelets
- stored in vesicles with ATP
- no synthesis
Where is serotonin located in the CNS?
Cell bodides in midbrain raphe nuclei (2%)
– project to hypothalamus, neostriatum, limbic forebrain, neocortex, medulla, and spinal cord
- synthesis, storage, and release
- rapid turn over (<4 hours)
Of the serotonin receptors, which is NOT a GPCR?
5-HT3 – ligand-gated Cation channel
What is the effector pathway of 5-HT1(A-E)?
Inhibition of adenylate cyclase
HT1A also opens K+ channels
What is the effector pathway of 5-HT2(A-C)?
Phosphoinositide hydrolysis
What is the effector pathway of 5-HT3?
Ligand-gated cation channel
What is the effector pathway of 5-HT4-7?
Activation of adenylate cyclase
5-HT5B unknown
What is the function of serotonin auto-receptors and what receptors are they like?
Decrease serotonin release
Like 5-HT1A and 5-HT1D
What serotonin receptor results in the inhibition of adenylate cyclase?
5-HT1(A-E)
What serotonin receptor results in phosphoinositide hydrolysis?
5-HT2(A-C)
What serotonin receptor is a ligand-gated cation channel?
5-HT3
What serotonin receptor activates adenylate cyclase?
5HT4-7
What is the function of serotonin the in GI system?
Causes contraction of G.I. smooth muscle including esophagus, stomach and intestine, increasing tone, peristalsis, and diarrhea
What receptor induces emesis?
5-HT3 in GI tract and brain
What is the carcinoid syndrome?
Serotonin secreting tumors and bradykinin of enterochromaffin cells
– cause severe diarrhea and asthma
Tx: 5-HT antagonist or somatostatin analog that blocks the secretion of all mediators from tumor
What is the effect of serotonin on large arteries and veins in most vascular beds and cranial blood vessels?
Potent vasoconstriction
What is the effect of serotonin on smooth muscle cells and the brain?
Vasoconstriction
What serotonin receptors are found on smooth muscle cells?
5-HT2 receptors
What serotonin receptors are found in the brain?
5-HT1D
What is the Bezold-Jarish reflex and what is activated by serotonin?
Serotonin is a powerful activator of chemoreceptors in coronary vasculature which activates afferent vagal nerve endings.
The response is bradycardia, hypotension and hypoventilation.
What is the effect of serotonin on chemoreceptors in coronary vasculature?
Activation!
Bezold-Jarish reflex: Bradycardia, hypotension, and hypoventilation
What is the effect of serotonin on platelets?
Active uptake of serotonin from circulation results in platelet aggregation
As a neurotransmitter, serotonin may be involved in what functions/perceptions/regulations?
- sensory perception (LSD)
- sleep
- temperature regulation
- neuroendocrine regulation (release ACTH, GH, prolactin, TSH, FSH and LH)
- learning and (short-term) memory
- pain perception
- drug abuse
- emesis (5-HT3 receptors)
- Mental Illness:
- Affective disorders
- Schizophrenia
- Obsessive-compulsive disorder
- Anxiety disorders (5-HT1A receptors)
- Aggressive behavior
What types of drugs treat affective disorders?
Serotonin Specific Reuptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake inhibitors (SNRIs)
What types of drugs treat schizophrenia?
Atypical antipsychotics
What types of drugs treat obsessive-compulsive disorder?
Serotonin Specific Reuptake Inhibitors (SSRIs)
Activation of what serotonin receptor results in anxiety?
5-HT1A
Lysergic Acid Diethylamide
Serotonin Agonist
Full or partial agonist at 5-HT2 receptors
– Potent hallucinogen
What drug is a full or partial agonist at 5-HT2 receptors and is a potent hallucinogen?
Lysergic Acid Diethylamide
Buspirone
Serotonin Agonist
Partial agonist at 5-HT1A receptors
Tx: Anti-anxiety
What drug is a partial agonist at 5-HT1A and is an antianxiety agent?
Buspirone
Sumatriptan
Serotonin Agonist
- 5-HT1D receptors on cerebral blood vessels
- inhibit release of vasoactive peptides– Calcitonin gene related peptide (CGRP)
- promote vasoconstriction
Tx: migraine headaches
Side effects: n/v, angina, dizziness and flushing
What drug binds 5-HT1D on cerebral blood vessels to treat migraine headaches?
Sumatriptan
Fluoxetine
Indirect Serotonin Agonist
Serotonin specific Reuptake Inhibitor
- blocks active reuptake of serotonin into neurons– increases amount of serotonin at synapse
Tx: affective disorders, obsessive-compulsive disorders, panic attacks, etc.
What drug blocks the active reuptake of serotonin?
Fluoxetine
Serotonin Specific Reuptake Inhibitors (SSRIs)
What do SSRIs treat?
Ex. Fluoxetine
Tx: affective disorders, obsessive-compulsive disorders, panic attacks, etc.
Phenelzine
Indirect Serotonin Agonist
Monoamine Oxidase Inhibitors
– block metabolism of serotonin, NE, and DA
Tx: affective disorders and narcolepsy
Side effect: hypertensive crisis
What do monoamine oxidase inhibitors block?
Black metabolism of serotonin, NE, and DA
What indirect serotonin agonist can result in a side effect of hypertensive crisis?
Phenelzine
What drug can be used to treat narcolepsy and affective disorders?
Phenelzine
Cyproheptadine
Serotonin Antagonist
- 5-HT2 receptor antagonist; H1 antagonist
Tx: skin allergies, pruritus, and urticaria. Tx of carcinoid
What drug is a 5-HT2 receptor antagonist?
Cyproheptadine
What drug is used in treatment of skin allergies like pruritus and utricaria as well as carcinoid?
Cyproheptadine
Ondansetron
Serotonin antagonist
- 5-HT3 receptor antagonist
- acts at both GI and brain receptors
Tx: chemotherapy induced n/v
What drug is used to treat chemotherapy induced n/v?
Ondansetron
What drug works on both 5-HT3 receptors of the CNS and GI?
Ondansetron
Alosetron
Serotonin Antagonist
- selective 5-HT3 antagonist
Tx: diarrhea predominantly from IBS in women
AEs: severe GI
- Restricted in women
What drug is a selective 5-HT3 antagonist?
Alosetron
What drug is used to treat diarrhea predominantly from IBS in women?
Alosetron
What drug is a target for insomnia treatment because it entrains the circadian clock?
Melatonin
