5-HT Receptor Functions in GI and CNS

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Questions and Answers

What is a characteristic effect of D-Lysergic acid Diethylamide (LSD) at low doses?

Elicits sensory distortion and hallucinations (correct)

Causes sedation and motor incoordination

Increases the firing rate of raphe cells

Produces antagonist effects on 5-HT2A receptors

What type of receptor does 8-OH-DPAT primarily activate?

5-HT1D receptor

5-HT4 receptor

5-HT1A receptor (correct)

5-HT2A receptor

How does sumatriptan affect cerebral blood vessels?

Has no effect on cerebral blood vessels

Increases the firing rate in terminal fields

Constricts cerebral blood vessels (correct)

Causes dilation of cerebral blood vessels

What is the primary action of cisapride in the gastrointestinal system?

Increases gastrointestinal motility Signup and view all the answers

Which statement best describes tegaserod's potency compared to endogenous serotonin?

It is one-fifth as potent as endogenous serotonin Signup and view all the answers

Which receptor is responsible for causing contraction of the intestinal smooth muscle?

5-HT2A Signup and view all the answers

What is the effect of 5-HT1A on acetylcholine release in the presynaptic ganglion cells?

It inhibits acetylcholine release. Signup and view all the answers

Which of the following receptors mediate fast depolarization in the postsynaptic ganglion cells?

5-HT3 Signup and view all the answers

What is the role of 5-HT4 in the gastrointestinal tract?

Promotes the release of acetylcholine. Signup and view all the answers

Which receptor primarily mediates the stimulation of nociceptive sensory nerve endings?

5-HT3 Signup and view all the answers

Which receptor is associated with increasing K+ conductance and causing hyperpolarization in raphe cells?

5-HT1A Signup and view all the answers

Which effect does serotonin have on gastric secretion?

Inhibits gastric secretion. Signup and view all the answers

How does 5-HT affect respiration when administered in large doses?

Results in transient apnea. Signup and view all the answers

What is one potential mechanism of action for clozapine in the treatment of schizophrenia?

It may exert inverse agonist activity at 5-HT2A/2C receptors. Signup and view all the answers

Which type of medication is ondansetron classified as?

Selective 5-HT3 antagonist Signup and view all the answers

Which of the following agents acts as an SNRI?

Duloxetine Signup and view all the answers

What is the main action of monoamine oxidase inhibitors (MAOIs)?

They inhibit the inactivation of serotonin, dopamine, and norepinephrine. Signup and view all the answers

What distinguishes SSRIs from TCAs in their mechanism of action?

SSRIs primarily block serotonin reuptake. Signup and view all the answers

Which class of drugs inhibits both serotonin and norepinephrine reuptake?

Tricyclic antidepressants Signup and view all the answers

Which medication is considered a serotonin antagonist and reuptake inhibitor (SARI)?

Trazodone Signup and view all the answers

What is a notable characteristic of atypical antipsychotic drugs like risperidone compared to classical neuroleptics?

They typically reduce incidence of extrapyramidal side effects. Signup and view all the answers

What is a significant characteristic of the 5-HT1F receptor subtype in relation to blood vessels?

It has no effect on blood vessel constriction. Signup and view all the answers

Which of the following compounds has undergone termination of development due to hepatic toxicity?

LY334370 Signup and view all the answers

Which drug is categorized as a second-line treatment for patients with cardiovascular risk who do not respond to triptans?

Lasmiditan Signup and view all the answers

Which statement correctly describes the binding affinity of sumatriptan and naratriptan?

They bind to the 5-HT1F receptor with high affinity. Signup and view all the answers

What is the significance of the 5-HT1F receptor in the context of migraine treatment?

It has been proposed as a major target due to its role in modulating neurogenic inflammation. Signup and view all the answers

What is the mechanism of action of triptans in migraine treatment?

5-HT1B/1D/1F receptor agonist Signup and view all the answers

Which drug is a 5-HT1 receptor partial agonist used for acute migraine treatment?

Ergotamine Signup and view all the answers

Which of the following is a notable side effect of triptans?

Coronary vasoconstriction Signup and view all the answers

What is the primary challenge with controlling delayed-phase CINV after chemotherapy?

Poorly controlled nausea and delayed-phase CINV Signup and view all the answers

Which of the following drugs could be recommended for patients experiencing CINV after moderately emetogenic chemotherapy?

NK1 RA and dexamethasone Signup and view all the answers

What does the new formulation granisetron extended-release subcutaneous (GERSC) primarily aim to address?

Extend efficacy of 5-HT3 receptor antagonist into delayed phase Signup and view all the answers

Why are triptans contraindicated in patients with cardiovascular disease?

They cause vasoconstriction due to 5-HT1B receptor activation Signup and view all the answers

Which of the following statements about the role of 5-HT in migraine treatment is true?

5-HT1F receptor agonists have been developed as new treatments. Signup and view all the answers

Study Notes

5-HT Receptor Function in the GI Tract

5-HT released from enterochromaffin cells regulates GI function.
5-HT3 receptors promote 5-HT release, while 5-HT4 receptors inhibit 5-HT release.
5-HT2A receptors cause contraction of intestinal smooth muscle.
5-HT2B receptors cause contraction of stomach fundus smooth muscle.
5-HT4 receptors cause contraction of the esophagus.
In presynaptic ganglion cells, 5-HT4 promotes acetylcholine (Ach) release, while 5-HT1A inhibits Ach release.
In postsynaptic ganglion cells, 5-HT3 causes fast depolarization, and 5-HT1 causes slow depolarization.
Enteric 5-HT triggers peristaltic contraction in response to Ach, sympathetic nerve stimulation, increased intraluminal pressure, and lowered pH.

5-HT Function in the CNS

5-HT excites some neurons and inhibits others.
5-HT1A and 5-HT1B receptors increase potassium (K+) conductance and cause hyperpolarization of raphe cells.
5-HT2A and 5-HT2C receptors decrease K+ conductance and cause slow depolarization on the prefrontal cortex and nucleus accumbens.
5-HT2A receptors also act on calcium (Ca+2)-activated membrane currents, enhancing neuronal excitability and potentiating the response to excitatory signals like glutamate.
5-HT3 receptors reflect direct gating of sodium (Na+) and K+ ion channels, causing fast depolarization in the CNS, sympathetic ganglia, primary afferent parasympathetic and sympathetic nerves, and enteric neurons.
5-HT4 receptors are coupled to the activation of adenylate cyclase and elicit a slow neuronal depolarization mediated by an increase in K+ conductance.

5-HT Function in Nerve Endings

5-HT stimulates nociceptive (pain-mediating) sensory nerve endings, an effect mediated by 5-HT3 receptors.
Injected into the skin, 5-HT causes pain.
Systemically administered, 5-HT elicits a variety of autonomic reflexes through stimulation of afferent fibers in the heart and lungs.
5-HT also inhibits transmitter release from adrenergic neurons in the periphery.

5-HT Function in Glands

5-HT inhibits gastric secretion but increases mucus production.
This contributes to its ulcer-protective properties.
5-HT's effects on other glandular secretions are not significant.

5-HT Function in Respiration

5-HT briefly stimulates respiration (mainly reflex from bronchial afferents) and causes hyperventilation.
However, large doses can cause transient apnea through the coronary chemoreflex.
Unlike benzodiazepines, 5-HT does not produce sedation, motor incoordination, or withdrawal effects.
5-HT does not interact with GABA A receptors, unlike benzodiazepines.

5-HT Receptor Agonists

D-Lysergic acid diethylamide (LSD):
- Non-selective ergot derivative agonist that alters human behavior.
- At low doses, it causes perception disturbances like sensory distortion and hallucinations, particularly affecting vision.
- Activates multiple 5-HT receptor subtypes, including 5-HT1A on raphe cell bodies, 5-HT2A/2C (likely responsible for its hallucinogenic effect), and 5-HT5-7 in specific brain areas.
- Antagonizes 5-HT2A receptors in the ileum.
8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT):
- Selective 5-HT1A agonist.
- Reduces the firing rate of raphe cells by activating 5-HT1A autoreceptors and inhibits neuronal firing in terminal fields by directly interacting with postsynaptic 5-HT1A receptors.
Sumatriptan:
- Selective 5-HT1D/1B agonist along with other triptans.
- Constricts cerebral blood vessels and is a highly effective treatment for acute migraine attacks.
- Contraindicated in patients with ischemic heart disease (IHD) due to coronary artery spasm.
Cisapride:
- Prokinetic drug that increases gastrointestinal motility and is a selective 5-HT4 agonist.
- Renzapride is more selective for 5-HT4 receptors.
- Binds and activates 5-HT4 receptors on myenteric neurons, leading to acetylcholine release and contraction of gastric smooth muscle.
Tegaserod:
- A selective partial agonist on the 5-HT4 receptor.
- One-fifth as potent as endogenous serotonin.
- Accelerates gastric emptying, colonic filling, and colonic transit by stimulating GI smooth muscles.
Clozapine:
- May exert inverse agonist activity at cerebral 5-HT2A/2C receptors, potentially explaining its effectiveness in resistant cases of schizophrenia.
- Reduced incidence of extrapyramidal side effects compared to classical neuroleptics.
- Other atypical antipsychotic drugs include risperidone, quetiapine, and olanzapine.

5-HT Receptor Antagonists

Ondansetron:
- Prototype of selective 5-HT3 antagonists.
- Highly effective in controlling nausea and vomiting following administration of emetic anticancer drugs and radiotherapy.
- Other drugs in this class include granisetron and tropisetron.
- Used to control cancer chemotherapy/radiotherapy-induced vomiting and are effective in postoperative nausea and vomiting (PONV).

Drugs Affecting Serotonergic Neurotransmission

Degradation inhibitors:
- Monoamine oxidase (MAO) inhibitors:
  - MAO is a key enzyme for the inactivation of serotonin, dopamine, and norepinephrine.
  - Used in the treatment of depression (tranylcypromine, phenelzine) and Parkinson's disease (selegiline).
Storage inhibitors:
- Dextromethorphan and Reserpine:
  - Interfere with the ability of synaptic vesicles to store monoamines.
  - Displace serotonin, dopamine, and norepinephrine from their storage in presynaptic nerve terminals.
Reuptake inhibitors:
- Serotonin-norepinephrine reuptake inhibitors (SNRIs):
  - Block serotonin and norepinephrine reuptake in a concentration-dependent manner.
  - Agents include venlafaxine and duloxetine.
  - Effective in treating depression.
- Selective serotonin reuptake inhibitors (SSRIs):
  - Block serotonin reuptake.
  - Enhance postsynaptic neuronal activity.
  - Used to treat depression and anxiety disorders.
  - Examples include citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and vilazodone.
- Serotonin antagonist and reuptake inhibitors (SARIs):
  - Used as antidepressants, anxiolytics, and hypnotics.
  - Inhibit serotonin, dopamine, and norepinephrine reuptake.
  - Currently marketed SARIs belong to the phenylpiperazine class of compounds.
  - Examples include lorpriprazole, trazodone, nefazodone, and mepiprazole.
- Tricyclic antidepressants (TCAs):
  - Act by inhibiting reuptake of 5-HT and norepinephrine from the synaptic cleft by blocking 5-HT and norepinephrine reuptake transporters.
  - Increase the postsynaptic response.
  - Examples include imipramine, desipramine, and trimipramine.

Antimigraine Drugs

Triptans:
- Examples: sumatriptan, amlotriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan.
- Used for acute migraine treatment.
- Mechanism of Action (MOA): 5-HT1B/1D/1F receptor agonist.
- Constricts large arteries and inhibits trigeminal nerve terminals.
- Side Effects: coronary vasoconstriction, dysrhythmias.
- Contraindication: coronary heart disease.
Ergotamine:
- Used for acute migraine treatment.
- MOA: 5-HT1 receptor partial agonist; Also affects α adrenoreceptors. Vasoconstrictor. Blocks trigeminal nerve transmission.
- Side effects: peripheral vasoconstriction, including coronary vessels. Nausea and vomiting. Contracts the uterus and may damage the fetus.

Pathophysiological Role of 5-HT

Chemotherapy-induced nausea and vomiting (CINV):
- Involves 5-HT3 receptor antagonism.
- CINV control remains challenging, particularly for moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC), especially delayed-phase CINV (24-120 hours after chemotherapy).
- HEC includes a four-drug regimen (5HT3 receptor antagonist, neurokinin 1 [NK1] receptor antagonist, dexamethasone, and olanzapine).
- A three-drug regimen (5HT3 receptor antagonist, NK1 receptor antagonist and dexamethasone) is recommended for some MEC regimens.
- 5HT3 receptor antagonists have significantly improved CINV in the acute phase (0-24 hours after chemotherapy), but their efficacy declines in the delayed phase.
- Newer formulations have been developed to extend 5-HT3 receptor antagonist efficacy into the delayed phase.
- Granisetron extended-release subcutaneous (GERSC), the most recently approved 5HT3 receptor antagonist, provides slow, controlled release of therapeutic granisetron concentrations for ≥5 days.

Advances in the Use of 5-HT

Novel acute treatment targets in Migraine:
- Novel targeted acute and preventive therapies are emerging, including ditans (5-HT1F receptor agonists), gepants (calcitonin gene-related peptide [CGRP] receptor antagonists) and anti-CGRP monoclonal antibodies (mAbs).
- Triptans are 5-HT1B/1D receptor agonists with some affinity for the 5-HT1F receptor subtype.
- They cause vasoconstriction due to 5-HT1B receptor activation, contraindicated in cardiovascular disease.
- Therefore, drug pharmacological studies have focused on the 5-HT1D and 5-HT1F receptors.
- However, trials of 5-HT1D agonists have not yielded promising results.
- Consequently, drug discovery programs shifted focus to the 5-HT1F subtype.
- This receptor subtype is found in the trigeminal ganglion, the trigeminal nucleus caudalis, and cephalic blood vessels. Importantly, activation of this receptor does not constrict blood vessels.
- Sumatriptan and naratriptan bind to the 5-HT1F receptor with high affinity.
- Based on these findings, 5-HT1F agonists have been developed and categorized as a new drug class: ditans.
- Preclinical studies of ditans suggest their involvement in modulating dural neurogenic inflammation and the trigeminovascular system, establishing the 5-HT1F receptor as a potential target for migraine treatment.
- Three compounds exist: LY 344864, LY334370, and lasmiditan.
- LY334370 development was terminated due to hepatic toxicity in animal models.
- Lasmiditan is likely to be approved as a second-line treatment for patients who fail with triptans or first-line anti-migraine treatment, particularly in those with cardiovascular risk.

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Description

Explore the complex roles of 5-HT receptors in the gastrointestinal tract and central nervous system. This quiz covers the mechanisms of action, receptor types, and their physiological effects, contributing to our understanding of neurotransmitter function. Test your knowledge on how these receptors interact with various cells and influence gastrointestinal motility and neuronal activity.