serotonin receptors and pharmacology

see also:

• serotonin physiology
• serotonin syndrome

• 6 sub-types: A-F;

• found in Raphe nuclei & hippocampus, medullary neurons ⇒ decr. BP;
  • ⇒ decr. cAMP ⇒ veno/arteriolodil. without EDRF;
• social cognitive component modulated by frontal & temporal cortices in conjunction with the hippocampus & mediated by 5HT1A and noradrenaline neurotransmission
  • drugs that influence 5HT1A function (buspirone) selectively affect performance on neuropsychological tests of memory and learning without affecting executive functions
• urapidil: agonist + alpha1-adrenergic blocker ⇒ anti-HT;
• buspirone:
  • partial agonist ⇒ slow-acting anxiolytic & antidepressant;
  • also pre-synaptic dopamine antagonist;
• flibanserin: agonist and antagonist at 5-HT2a ⇒ supposedly increases female libido

• found in substantia nigra, globus pallidus, & basal ganglia
• ? decr. adenylate cyclase & ? activates K channel (musc.like) ⇒ decr. NA release

• found in choroid, hippocampus & substantia nigra
• similar to H1 in that causes:
  • vasodilatation via incr. Plipase C ⇒ incr. EDRF from vasc. endoth.
  • but:
    • no capill.perm. effect in humans;
    • doesn't constrict arteries/veins;

• cerebral & middle menigeal Art vasoconstriction; CNS;
• decr. release of peptides from trigeminal N terminals;
• triptans
  • selective agonist 5-HT1Dz used to Rx migraine

• cortex & putamen, causes decr. cAMP

• cortex & hippocampus, causes decr. cAMP

• coupled to Plipase C → incr. [Ca]i;
• contracts veins, arteries, venules, but not arterioles (which are dilated by 5-HT1);
• stimulates platelet aggregation; incr. capill. permeability;
• ? involved in PRL release; neuroendocrine functions;

• found in platelets, smooth muscle, cerebral cortex
• prefrontal cortex role in cognitive processes such as behavioural inhibition, feelings of hopelessness?
• flibanserin: antagonist and agonist at 5-HT1a ⇒ supposedly increases female libido

• agonism of these receptors on cardiac valvular interstitial cells appears to be involved in serotonin-associated cardiac valvulopathy as shown with the non-selective serotonergic diet medications such as fenfluramine and dexfenfluramine.
• agonism at pulmonary smooth muscle cells may also be associated with pulmonary arterial hypertension

• activation decreases food intake via the propiomelanocortin system of neurons
• Lorcaserin:
  • selective 5-HT2C agonist with 15x more activity than on 5-HT2A receptors, and 100x more activity than on 5-HT2B receptors
  • under trial for obesity and weight management management in 2010¹⁾ - appears to reduce weight by ~6kg in 1 year compared with 2kg for a placebo with almost 50% of patients losing at least 5% body weight compared with only 20% of those on placebo.

• found in fundus of stomach.
• Cyproheptadine:
  • prominent 5-HT2 block on various sm.muscles thus useful in pruritus, cold urticaria but as 5-HT not involved in allergic responses the only benefit are from anti-H1 & anticholin. activity;
• Ketanserin:
  • Only 5-HT2 block (& alpha1, H1 & dopamine rec. block);
  • decr. 5-HT vasoconstriction (& alpha1 block decr. vasoc.)
  • incr.QT esp. if diuretics!
  • ⇒ decr. BP similar in degree to beta-block or diuretics;
  • ⇒ use as anti-HT & in vasospastic disorders but ? poor results;
• Pizotifen: (Sandomigran)
  • selective antagonist 5-HT2 & affinity 5-HT1C used to prevent migraine
• Mianserin:
  • 5-HT2 antagonist & actions @ H1, alpha1 receptors & pre-syn. alpha2 antag.;
• Ritanserin:
  • 5-HT2 antagonist only ? ⇒ anxiolytic?;

• ? via activation of a cation channel;
• found in area postrema, sensory & enteric nerves
• depolarisation of sensory nerves ⇒ pain, itch & if GIT ⇒ N/V;
• GIT myenteric plexus: antagonism ⇒ decr. bowel hypermotility & incr. gastric emptying;
• CNS: antagonism ⇒ anxiolytic & neuroleptic & block CTZ/vomiting centre;
• metoclopramide (Maxolon):
  • 5-HT3 antag. + 5-HT4 agonist + CNS dopamine antagonist;

• ondansetron:
  • more effective as anti-emetic in post-op vomiting or gastroenteritis than metoclopramide (Maxolon) or domperidone (Motilium) but more expensive
• dolasetron:
  • dose 12.5mg iv
• granisetron:
  • dose 1mg iv
• tropisetron:
  • dose 2mg iv

• found in CNS & myenteric neurons, smooth muscle;
• ⇒ incr. cAMP.
• GIT neuroexcitatory;
• CNS effects
• cardiac muscle stimulation
• cisapride:
  • selective 5-HT4 agonist with M2 agonist & 5-HT3 antagonist actions
  • can cause diarrhoea and increased gastric emptying BUT also risk of arrhythmias due to prolongation of QTc and thus no longer used
• prucalopride
  • a 5HT4 agonist introduced in Australia in 2011 (Resotrans) as a Rx for refractory constipation despite Rx over 6 months, however only 30% of patients will respond (vs ~10% responders to placebo)
  • usual dose 1-2mg once a day (no extra benefit at higher doses)
  • mainly excreted unchanged in urine
  • may cause headache, nausea, abdominal pain and diarrhoea, especially at the start of Rx
  • does not appear to affect QTc
  • C/I if ileus, obstruction, inflammatory bowel disease (IBD), or post-op bowel surgery
  • avoid pregnancy but beware diarrhoea may reduce effectiveness of OCP!!
  • cease if not effective after 4 weeks Rx

• found in brain; unknown mechanism;

• found in brain; ⇒ incr. cAMP.
• clozapine:
  • partially selective 5HT7 antagonist.

• see Ergot alkaloids

• used as new antidepressants;
• see SSRI/SNRI antidepressants
• Fluoxetine:
  • long acting with active metabolite; elimination T« days-wks;
  • 20-40mg single dose/day as effective as 60-80mg/d;
  • dose-related side effects: N, nervousness, insomnia;
  • much less anticholinergic, wt. gain, sedation, cardiotoxic cf tricyclics;
  • as effective as & similar onset action to tricyclics & MAOI;
  • interactions with: cimetidine; tricyclics;

• tricyclics & cocaine inhibit neuronal amine uptake: ie. of both 5-HT & NA.
• MAOI inhibit the metabolism of 5-HT.
• reserpine releases & depletes 5-HT stores;
• amphetamines incl. Ecstasy, release 5-HT & interfere with its synthesis;