5-HT (A*)

Question 1

Describe the synthesis pathway of 5-HT.

Answer 1

5-HT synthesis pathway:

1 - L-tryptophan is converted into 5-hydroxy-L-tryptophan by the action of tryptophan hydroxylase.

• This enzyme is a phenotypic marker for a cell that can generate 5-HT (it is not expressed in all cells).

2 - 5-hydroxy-L-tryptophan is converted into 5-hydroxytryptamine (5-HT) by the action of 5-hydroxy-L-tryptophan decarboxylase.

• This enzyme is expressed in almost every cell.

Question 2

Describe the distribution of 5-HT in the body.

Answer 2

1 - 90% of the body’s 5-HT is in the GIT.

• Most of the GIT’s 5-HT is in enterochromaffin cells, the rest is in enteric neurones.

2 - Some 5-HT is found in platelets at a very high concentration (released after platelet activation).

3 - The rest is found in neurones of both the PNS and CNS.

Question 3

List the 5-HT receptor subtypes.

Are the subtypes ionotropic or metabotropic?

If they are metabotropic, what alpha subunit are they coupled to?

Answer 3

1 - 5-HT1 A-F.

• These are Gi/o GPCRs (inhibitory).

2 - 5-HT2 A-C.

• These are Gq GPCRs (excitatory).

3 - 5-HT3.

• These are ionotropic receptors (excitatory).

4 - 5-HT4.

• These are Gs GPCRs (excitatory).

5 - 5-HT5 A-B.

• These are Gi/o GPCRs (inhibitory).

6 - 5-HT6.

• These are Gs GPCRs (excitatory).

7 - 5-HT7.

• These are Gs GPCRs (excitatory).

Question 4

What is the cellular effect of Gi/o GPCR subunits?

What is therefore the effect of Gi/o GPCR subunits on neurotransmission?

Answer 4

• Gi/o GPCR subunits decrease cAMP.
• Therefore, Gi/o subunits, such as those coupled to 5-HT1 and 5-HT5 receptors, are inhibitory.
• Remember Gs and Gq cause excitation by increasing intracellular Ca2+ by cAMP and IP3 respectively.

Question 5

What is unique about the genes that encode 5-HT1 receptors?

What is the functional relevance of this?

Answer 5

• Genes encoding 5-HT1 receptors are intronless genes.

- This is functionally relevant because it means that there are no splice variants of 5-HT1 receptors.

Question 6

How many transmembrane domains do all GPCRs have?

Answer 6

All GPCRs have 7 transmembrane domains.

Question 7

Which ions pass through the 5-HT3 ion channel?

Which ions undergo influx and which ions undergo efflux?

Answer 7

The 5-HT3 ionotropic receptor uses Na+ (influx), Ca2+ (influx) and K+ (efflux).

Question 8

Half A*:

Describe the structure of the 5-HT3 receptor.

Answer 8

• The 5-HT3 receptor is an ionotropic receptor that has a very similar structure to nicotinic AChRs.
• It is composed of 5 subunits.
• Each subunit is one of the subtypes A-E, but at least 2 must be A (5-HT3A subunits can form homomeric receptors, meaning all 5 subunits are composed of 5-HT3A).
• Each subunit comprises:

1 - An extracellular N-terminal domain which, in A subunits, contributes to the orthosteric ligand-binding site (see A* points below).

2 - A transmembrane domain consisting of four interconnected alpha helices (M1-M4), with the extracellular M2-M3 loop involved in the gating mechanism lining the ion pore, and an intracellular domain between M3 and M4 involved in receptor trafficking (movement of the newly synthesised receptor within the neurone) and regulation.

3 - A short extracellular C-terminus.

A*: The 5-HT3 receptor is part of the cys loop LGIC superfamily.

A*: The orthosteric binding site is believed to be between two adjacent A subunits (hence there must be at least 2 A subunits).

A*: Subunits A,C,E,D interact with a ‘molecular chaperone’ known as RIC‐3.

• RIC-3 primarily interacts with 5-HT3A, enhancing surface expression of homomeric 5-HT3A receptors.

A*: The C-terminus of the 5-HT3A subunit is required for posttranslational modification and folding, cell surface expression and ligand binding affinity.

A*: The single channel conductance of homomeric 5-HT3A receptors is relatively low compared to that of heteromeric 5-HT3A/B receptors (Brady et al., 2007). This can be used to differentiate 5-HT3 receptors by their electrophysiological properties.

Question 9

Describe the pattern of gene expression of 5-HTA and 5-HT5B receptors.

Answer 9

• In humans, 5-HT5A receptors have been identified in glioma cells.
• In rats, 5-HT5A receptors have been identified in layer 5 pyramidal neurones.
• 5-HT5B receptors aren’t expressed in humans.
• This is because there is a stop codon in the gene encoding for 5-HT5B receptors.
• This means that only a truncated version of the 5-HT5B receptor is expressed, but the function of the truncated protein is unknown.

Question 10

List 4 functions of 5-HT receptor-targeting drugs.

Which 5-HT receptor subtypes are targeted to achieve these functions?

Are the drugs that achieve these effects agonistic or antagonistic?

Answer 10

1 - Anxiolytics (5-HT1A partial agonist).

2 - Migraine drugs (5-HT1B and 5-HT1D agonists or 5-HT2A antagonists).

3 - Antiemetics (5-HT3 antagonists).

4 - Laxatives (5-HT4 agonists).

Question 11

Which 5-HT receptor subtype is found exclusively in neurones in the brain?

Answer 11

5-HT6 receptors are found exclusively in neurones in the brain.

Question 12

What is the relationship between 5-HT release and anxiety?

Answer 12

There is a positive relationship between 5-HT release and anxiety.

Question 13

What is 8-OH DPAT?

What was the idea behind its mechanism of action?

Why is it not used clinically?

Answer 13

• 8-OH DPAT is an agonist for 5-HT1A receptors that was developed as an anxiolytic.
• The idea was that by binding to somatodendritic 5-HT1A receptors, it would cause inhibition and therefore turn off 5-HT-releasing neurones, reducing anxiety.
• It isn’t used because it actually turns out to increase anxiety because it also activates postsynaptic 5-HT1A receptors, which are anxiogenic.

Question 14

How can 5-HT1A receptors be targeted to produce an anxiolytic effect?

Give an example of a drug that does this.

What is the advantage of using this drug over other anxiolytics?

Answer 14

• Somatodendritic 5-HT1A receptors have a high receptor reserve.
• This means that a partial agonist has the effect of an agonist at somatodendritic 5-HT1A receptors.
• Postsynaptic 5-HT1A receptors have a low receptor reserve.
• This means that a partial agonist has the effect of an antagonist at postsynaptic 5-HT1A receptors (causes a reduction in response relative to a full agonist).
• Therefore, a partial agonist for 5-HT1A receptors can be used to produce an anxiolytic effect by blocking postsynaptic 5-HT1A receptors (these receptors cause anxiety) but stimulating somatodendritic 5-HT1A receptors (to turn off 5-HT neurones).
• Buspirone is an example of a partial 5-HT1A receptor agonist that does this.
• The advantage of buspirone over other anxiolytic drugs is that it doesn’t cause dependence.

Question 15

What are migraine attacks (A*)?

Describe the pathophysiology of migraines (according to the platelet hypothesis of migraines).

Answer 15

Migraine definition (A*)

• Migraines occur in 4 stages:

1 - The prodromal phase, which often precedes the headache stage by numerous hours, is characterised by highly variable symptoms. Common example include disturbed GIT motility, mood changes and lethargy.

2 - The shorter aura stage is primarily accompanied by visual disturbances, such as flashes of light and blurred vision.

3 - The headache stage is characterised by pulsating headaches, usually lateralised and often lasting for hours. The headache is usually accompanied by vomiting, increased sensitivity to light (photophobia) and sound (phonophobia).

4 - The headache stage terminates in the resolution stage, where symptoms slowly subside.

Pathophysiology of migraines (according to the platelet hypothesis of migraines):

1 (A*) - Patients vulnerable to migraines have abnormally low basal 5-HT levels. This predisposes to migraine by inducing receptor sensitivity (see card 32 for evidence - better to introduce this point using evidence).

2 - Platelets release 5-HT in cerebral vessels.

3 - The 5-HT binds to sensitised 5-HT2A receptors in the vessel wall, causing excessive vasoconstriction.

• This vasoconstriction explains why some people experience visual disturbances before the onset of the migraine.

4 - A compensatory mechanism causes vasodilation to restore cerebral perfusion.

5 - Overcompensation of this vasodilation results in high pressure being applied to the surrounding sensory nerves, causing pain.

See A card 24 in neuropeptides lecture for details on CGRP in migraines.

See A* card 32 for evidence.

Question 16

List 2 treatments for migraines.

Briefly describe the mechanism of action for each.

Answer 16

Treatments for migraines include:

1 - 5-HT2A receptor antagonists such as pizotifen.

• These reduce the vasoconstriction in cerebral vasculature, and therefore prevent the overcompensatory vasodilation that causes the pain.
• This must be taken chronically since it is a prophylactic drug. This means they must be taken at the expense of suffering the side effects.

2 - 5-HT1B and 5-HT1D agonists such as sumatriptan.

• Triptans bind to 5-HT1B receptors in vessel walls and 5-HT1D (both inhibitory) receptors in sensory nerves.
• In the vessel wall, the 5-HT1 receptors cause a reduction in cAMP and therefore a reduction in vasodilation.
• Triptans also inhibit sensory nerve stimulation.
• These drugs can simply be taken at the onset of the migraine.
• But see A* card 24 in neuropeptides lecture for details on CGRP-based drugs.

Question 17

Which 5-HT receptor ligands are used as antiemetics?

Describe the mechanism of action for these drugs as antiemetics.

Answer 17

• 5-HT3 receptor antagonists such as ondansetron and palonosetron are used as antiemetics.

1 - Inflammation in the GIT results in the degranulation of enterochromaffin cells, which are densely packed with 5-HT.

2 - This 5-HT stimulates 5-HT3 receptors (excitatory) on the vagus nerve in the GIT, and also enters the bloodstream.

3 - The vagus nerve sends serotonergic axons to the chemoreceptor trigger zone in the brainstem.

4 - The chemoreceptor trigger zone comprises the area postrema and the nucleus tractus solitarius. Stimulation of 5-HT3 receptors in this area causes emesis (vomiting).

• 5-HT3 receptor antagonists antagonise both the 5-HT3 receptors on vagal afferents and in the chemoreceptor trigger zone directly to prevent emesis.

Question 18

Which 5-HT receptor ligands are used as laxatives?

Describe the mechanism of action for these drugs as laxatives.

Answer 18

• 5-HT4 agonists such as prucalopride and naronapride are used as laxatives.

1 - 5-HT4 agonists bind to 5-HT4 receptors on intrinsic primary afferent neurones (IPAN) in the GIT, causing excitation.

2 - IPAN neurones stimulate muscarinic motoneurones in the GIT.

3 - Excitation of muscarinic neurones in the GIT increases peristalsis, causing a laxative effect.

Question 19

A*:

Where are 5-HT6 receptors expressed?

What is their role in the brain?

Give an example of a 5-HT6-targeting drug.

Answer 19

• The 5-HT6 receptor is expressed in the brain, specifically:

1 - Olfactory tubercle (includes the olfactory cortex and ventral striatum).

2 - Entorhinal cortex.

3 - Nucleus accumbens.

4 - Hippocampus.

5 - Molecular layer of the cortex.

• 5-HT6 receptors have a neuromodulatory role in cholinergic and glutamatergic transmission.
• In rats, 5-HT6 receptor antagonists were shown to improve learning, and memory was improved in the water maze.
• Hence there is a role for these drugs in cognitive disorders such as Alzheimer’s. For example, latrepirdine is an antihistamine that has also been found to be a 5-HT6 antagonist, and is used as an adjunct therapy in cognitive disorders.
• The 5-HT6 receptor shows affinity for antipsychotic and antidepressant drugs, meaning the receptor might be a potential target for disorders such as schizophrenia and anxiety.

Question 20

A*:

What are GPCR-interacting proteins (GIPs)?

How do they affect 5-HT transmission?

What is the potential for targeting GIPs?

List 2 other proteins that have modulatory functions on 5-HT transmission.

How do these proteins affect 5-HT transmission?

Answer 20

• GPCR-interacting proteins (GIPs) are proteins that influence the properties of metabotropic 5-HT receptors.
• They do this by forming molecular complexes known as receptosomes with the various domains of the 5-HT receptors, the primary interaction site being the C-terminus. The effects of these complexes include:

1 - Directing the downstream effects of 5-HT transmission towards a specific cellular process.

2 - Influencing trafficking of newly synthesised receptors within the cell.

3 - FIne tuning signalling pathways.

• GIPs are emerging targets for neuropsychiatric disorders such as addiction and affective disorders.
• Two other proteins that modulate 5-HT GPCRs are GPCR kinases and beta arrestins.
• These proteins are thought to attenuate 5-HT signaling.

Question 21

A*:

Where are 5-HT7 receptors expressed?

What is the function of 5-HT7 receptors?

What is the potential for drugs targeting 5-HT7 receptors?

Answer 21

• 5-HT7 receptors are expressed in:

1 - Smooth muscle.

2 - Mesocorticolimbic pathway.

3 - Thalamus.

4 - Hypothalamus.

5 - Cortex.

• 5-HT7 receptors are thought to potentiate glutamatergic neurotransmission by phosphorylating AMPA receptors (Andreetta et al. 2016).
• 5-HT7 receptors are potential targets for various neuropsychiatric disorders, namely depression, but currently there is little evidence for the clinical efficacy of 5-HT7 receptor-targeting antidepressants.

Question 22

A*:

List 2 examples of allosteric modulation of 5-HT receptors.

How do these examples of allosteric modulation affect 5-HT transmission?

Answer 22

Examples of allosteric modulation of 5-HT receptors:

1 - Ethanol potentiates 5-HT3 transmission by increasing receptor affinity for 5-HT.

• The potentiation reduces with increasing 5-HT concentration, suggesting that the effect of ethanol at the receptor is to increase the affinity of the 5-HT3 receptor for 5-HT rather than receptor efficacy (Parker et al. 1996).

2 - General anaesthetics such as ketamine potentiate 5-HT3 transmission, even below the minimum alveolar concentrations.

• This is thought to be by increasing efficacy by modulating probability of channel opening.
• This suggests that 5-HT3 transmission could have a general anesthetic action.
• This is a possible explanation for postoperative nausea - 5-HT3 agonists cause emesis. Therefore, 5-HT3 antagonists are given prophylactically to prevent this.
• The allosteric site of general anaesthetics is different to alcohol, since it was shown that their effects were able to be superimposed (Parker et al. 1996).

Question 23

A*:

List 2 withdrawn serotonergic treatments for IBS.

How do they work?

Why were they withdrawn?

Give an example of a potential serotonergic therapy for IBS.

Why is this better?

Answer 23

• Previously, 5-HT3 antagonists such as alosetron, were used to treats IBS with diarrhoea, and 5-HT4 agonists such as tegaserod, were used to treat IBS with constipation.
• Like 5-HT4 receptors, 5-HT3 receptors are involved in controlling GIT motility. In enteric neurones, these receptors are likely heterometric 5-HT3A/B receptors (Michel et al., 2005). 5-HT3 receptors are located on vagal afferents (as described in the antiemesis card).
• IBS patients are thought to have overexpression of 5-HT3 receptors in the GIT, resulting in colonic distension, causing abdominal pain.
• 5-HT3 antagonists prevent excitation of GIT motility. They also disturb nociception in primary sensory neurones in the GIT. Thus, they exert both an antidiarrhoeal and antinociceptive effect.
• The exact mechanism by which 5-HT4 agonists reduce the symptoms of IBS is not clear, but their laxative effect is thought to be due to promoting GIT motility by stimulating IPANs (see card 18).
• Alosetron was found to cause ischaemic colitis and severe constipation, and tegaserod cause was found to cause cardiovascular side effects, so both were withdrawn.
• The 5-HT3A and 5-HT3B partial agonist CSTI-300 has been shown to relieve symptoms of IBS.
• Since 5-HT3 partial agonists like CSTI-300 do not cause the same degree of receptor blockade as full antagonists such as alosetron, the probability of adverse side effects is lower.

Question 24

A*:

What is the primary site in the brain for 5-HT synthesis?

Is 5-HT able to cross the blood-brain barrier?

Answer 24

• There are 9 serotonergic nuclei in the midline of the midbrain, B1-9, known as the raphe nuclei. These are the primary site for 5-HT synthesis in the brain.
• 5-HT is able to cross the blood-brain barrier (remember this is how circulating 5-HT causes emesis at its central targets).

Question 25

A*:

Describe the role of 5-HT in reward.

Answer 25

• Ascending projections from the raphe nuclei are extensive, and overlaps with dopaminergic reward pathways in the limbic system (Hayes et al., 2011).
• The monoamine theory of depression states that hypofunction of noradrenergic and serotonergic neurones underlies depression.
• Almost every 5-HT receptor subtype is in some way thought to influence reward, but inhuman studies are limited. Generally:
• Decreased expression of 5-HT1A has been linked with depression. 8-OH DPAT is a 5-HT1A agonist that increases reward at low doses, but decreases reward at high doses (see card 13).
• 5-HT1B receptor activation decreases reward. This is thought to be because 5-HT1B receptors inhibit VTA neurones. On the other hand, other studies have found that 5-HT1B receptor activation is associated with increased dopamine release in the mesocortical pathway.
• 5-HT2C receptor activation decreases reward. Antagonism of 5-HT2C receptors doesn’t increase reward by itself, but has been shown to enhance reward from other rewarding stimuli such as cocaine.
• 5-HT2A receptor activation (e.g. through psilocybin, a 5-HT2A agonist similar to LSD) increases reward, likely through upregulating BDNF in hippocampal neurones and thereby promoting neurogenesis.

Question 26

A*:

Describe the history of 5-HT discovery.

Answer 26

From Gershon (2013):

• In 1937, the Italian pharmacologist, Vittorio Esparmer, identified an unknown substance from a gut sample, which was found to be secreted by enterochromaffin cells.
• Soon after, a different group, Maurice Rapport and Irvine Page, began research on a seemingly different substance for its vasoconstrictor properties in the serum. Hence, Rapport and Page named the substance ‘serotonin’.
• Further work by Esparmer on the enterochromaffin-derived substance continued for a number of years. The substance was eventually termed ‘enteramine’ in 1954, however, unbeknown to Esparmer, enteramine and serotonin were soon found to be the same molecule.
• By this time, the term ‘serotonin’ was already well-established, and ‘enteramine’ failed to catch on.

Question 27

A*:

Describe the role of enterochromaffin cells in GIT motility.

Answer 27

From Gershon (2013):

History:

• In the mid 20th century, Edith Bülbring carried out a series of investigations into the role of 5-HT on the peristaltic reflex.
• The peristaltic reflex is a reflexive propagation of muscle contraction that occurs in the oral-aboral direction in the small and large intestine. Mechanical stimulation of these regions of the GIT results in 5-HT release, which signals via enteric nerves to induce peristalsis. This reflex facilitates movement of a bolus through the GIT for excretion.
• Bülbring proposed that mechanical stimulation of enterochromaffin cells results in 5-HT secretion, which in turn mediates contraction via action at IPANs.
• Bülbring demonstrated that application of 5-HT onto intestinal mucosa induces the peristaltic reflex, and that 5-HT secretion occurs in response to mechanical stimulation to enterochromaffin cells, implying that enterochromaffin cells mediate the peristaltic reflex by mechanically-stimulated secretion of 5-HT.
• However, the role of enterochromaffin cells in mediating the peristaltic reflex could not be decisively determined until enterochromaffin cells were in some way removed or disabled.
• Two variants of tryptophan hydroxylase (TPH), TPH1 and TPH2 mediate 5-HT synthesis in enterochromaffin cells and neurones respectively.
• Some years later in the 1960s, it was shown that TPH1 knockout mice demonstrate healthy constitutive GIT motility and peristaltic reflexes, implying that enterochromaffin cells do not play a significant role in GIT motility.
• Accordingly, more recent studies have demonstrated the relatively disabling effect of TPH2 knockout on GIT motility. Hence, the serotonergic neurones of the enteric nervous system likely play a more important role in GIT motility in spite of their relatively small contribution of total 5-HT.
• Hence, some believe that secretion of 5-HT by enterochromaffin cells is likely involved only in disorders of GIT motility, and that by depleting enterochromaffin cells of 5-HT, symptoms can be treated without disturbing normal GIT function.
• This would explain the results of a recent study in which a tryptophan hydroxylase inhibitor, LX1031, that acts locally in the GIT to reduce mucosal 5-HT production was found to improve symptoms of IBS without side effects of traditional 5-HT antagonists such as alosetron (Brown et al., 2011).

Question 28

A*:

Describe the role of 5-HT in urological disorders.

How might this be relevant for gastrointestinal disorders?

Answer 28

• Urological disorders such as interstitial cystitis (IC) and overactive bladder syndrome (OAB) are associated with peripheral sensitisation of nociceptors and pain fibres (including Aδ and C) that innervate the lower urinary tract.
• A recent study by Konthapakdee et al. (2019) demonstrated a 5-HT3-dependent enhancement of primary sensory afferent neurones innervating the urothelium. This might underlie the hypersensitivity of pain afferents in urological disorders.
• The sensory innervation of the gastrointestinal and urinary systems is mediated by many of the same nerves. For example, the hypogastric, pelvic and pudendal nerves respectively mediate the sympathetic, parasympathetic and somatic functions of both the colorectum and lower urinary tract.
• Innervation between these structures is paired in order to coordinate excretion from both systems.
• The fact that these afferent signals are carried by nerves that are common between the lower urinary tract and gastrointestinal system might explain the high comorbidity of urological and gastrointestinal disorders such as IC and IBS.
• This phenomenon is known as cross-organ sensitisation, and it suggests that 5-HT3-mediated sensitisation of afferents innervating the lower urinary system are responsible for both the urological and gastrointestinal symptoms in urological disorders.
• 5-HT3 antagonists may therefore have potential in treating both urological and gastrointestinal symptoms of urological disorders.

Question 29

A*:

Describe the role of 5-HT2C receptors in feeding behaviour.

Answer 29

• Lorcaserin is a 5-HT2C agonist that was shown to promote satiety in rats (Higgs et al., 2016).
• Also, when sibutramine, an SNRI appetite suppressant, was coadministered with a selective 5-HT 2C antagonist, the anorectic effect of sibutramine was reversed (Higgs et al., 2010).
• This implies that activation of 5-HT2C receptors has an anorectic effect.
• 5-HT2C is thought to activate POMC neurones of the anorectic pathway in the hypothalamus, increasing satiety.
• Lorcaserin promotes this action, resulting in an anorectic response.

Question 30

A*:

Describe the role of 5-HT6 receptors in feeding behaviour.

Answer 30

• Administration of a 5-HT6 receptor antagonist was found to reduce glucose intake in rats (Higgs et al., 2016).
• This implies that activation of 5-HT6 has an orexigenic effect.
• 5-HT6 is thought to activate neurones in the paraventricular nucleus, promoting anorectic physiological changes (see card 4).
• The 5-HT6 antagonist opposes this action, resulting in an orexigenic response.

Question 31

A*:

Describe the role of 5-HT in motor control.

Answer 31

Just an idea init. look at basal ganglia, cerebellum and thalamus

Question 32

A*:

Describe the evidence supporting the role of 5-HT in migraines.

Answer 32

Evidence supporting the role of 5-HT in migraines:

1 - Studies investigating venoconstriction in response to 5-HT administration in the vasculature of the hand found that vascular sensitivity to 5-HT-induced venoconstriction was greater in females compared to males (Panconesi et al., 1986). This aligns with the fact that women are 3 times more likely to suffer from migraines compared to men, as greater sensitivity to increases in 5-HT would indicate a basal hyposerotonergic status, predisposing to an excessive vascular response following 5-HT release from platelets.

2 - Vascular sensitivity to 5-HT-induced contraction is greater in the winter, and diminished in the summer (Pancoseni et al., 1986). This aligns with the finding that migraines follow a similar seasonal pattern, indicating that risk of migraine is correlated with vascular sensitivity to 5-HT-induced contraction.

3 - PET imaging has found that men exhibit faster 5-HT synthesis compared to men (Sakai et al., 2006). Therefore, although women and men show equal stores of central 5-HT, it has been hypothesised that women would show a decreased capacity to maintain 5-HT stores following utilisation of 5-HT, which in turn would predispose to migraine by inducing a hyposerotonergic state, resulting in 5-HT receptor sensitisation (Panconesi et al., 2008).

4 - 5-HT2A receptors can be upregulated by oestrogens (Cosgrove et al., 2007). This might explain the increased risk of migraines in women compared to men, as release of oestrogens would amplify the vasoconstriction induced by 5-HT, leading to migraine.

5 - 5-HT2A antagonists work as prophylaxis for migraines and 5-HT1B and 5-HT1D agonists work for symptomatic relief following onset of symptoms (see card 16 for drug examples).

But see A card 24 in neuropeptides lecture for details on CGRP in migraines.

Question 33

A*:

What causes 5-HT release from platelets?

Answer 33

• 5-HT release from platelets has been hypothesised to occur as a result of increased platelet aggregability caused by shear stress.
• Shear stress is the force that results from blood flow over the endothelium. Turbulent flow leads to changes in shear stress that result in platelet activation, mobilising platelet Ca2+ stores.
• In patients suffering from migraine, abnormalities in the vasculature may generate abnormal shear stress on platelets, resulting in pathological platelet activation and subsequent 5-HT release.
• Indeed, platelet hyperaggregability is a common finding in migraine sufferers, and numerous studies have demonstrated upregulation of circulating factors implicated in platelet aggregation, such as Von Willebrand factor, following a migraine. Furthermore, migraines are associated with stroke. This association would, in part, be explained by platelet hyperaggregability.
• Following these findings, antiplatelet drugs such as clopidogrel have undergone clinical trials as prophylactic anti-migraine drugs. Clopidogrel has shown high efficacy for reducing severity of migraines and has shown a good safety profile, but is associated with numerous side effects typical of antiplatelet drugs, such as diarrhoea, abdominal pain and increased bleeding.