5-HT (A*) Flashcards

Question

A*: Describe the role of 5-HT in reward.

Answer 1

- 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.

Answer 2

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.

Answer 3

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).

Answer 4

- 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.

Answer 5

- 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.

Answer 6

- 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.

Answer 7

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

Answer 8

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.

Answer 9

- 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.