Serotonin or 5-hydroxytryptamine

1. Serotonin or 5-hydroxytryptamine • Widely distributed amine (animals + plants) • In humans, present in GI enterochromaffin cells (90%), platelets and brain. • Synthesized from tryptophan (in diet) in two steps. • Platelets do not synthesize but take up from blood (active uptake process in platelets and nerve terminals). • Cell storage in granules similar to catecholamines.

2. (Rate limiting) OH COOH COOH Tryptophan hydroxylase C NH2 C NH2 N N In diet. Active CNS transport Tryptophan 5-Hydroxytryptophan 5-OH Tryptophan decarboxylase C COOH OH H N Aldehyde dehydrogenase C NH2 MAO 5-Hydroxy Indole Acetic Acid N 5-OH Indole Acetaldehyde 5-Hydroxytryptamine

3. Synthesis and Metabolism • Competition at the level of brain and neuronal uptake • Rate limiting enzyme not saturated usually • No end-product negative feedback • 5-OHTr decarboxylase same as DOPA decarboxylase • 5-OHIAA actively extruded from CNS (probenecid-sensitive) and excreted in urine.

4. Interference with the system • Inhibit uptake into CNS (other AA’s) • Inhibit synthesis: p-chlorophenylalanine (irreversible) • Inhibit neuronal re-uptake: cocaine, SSRA (e.g. fluoxetine), TCA (e.g. imipramine) • Inhibit storage-deplete: reserpine • Inhibit metabolism: MAO inhibitors • Promote release: p-chloroamphetamine - then depletes (e.g. fenfluramine to ↓ appetite) Non-selective

5. Serotonin Receptors • At least 15 types and subtypes • Multiple transduction mechanisms • 5HT-1A: role in anxiety/depression • 5HT-1D: role in migraine • 5HT-2: role in CNS various behaviors, and in cardiovascular system • 5-HT3: role in nausea and vomiting esp. due to Chemotherapy.

6. Endogenous Function • Central neurotransmitter • Precursor of melatonin • GI tract: uncertain; motility? • In carcinoid tumors: large amounts released leading to diarrhea, bronchoconstriction and edema • Platelets: 5-HT2 receptors → aggregation and vasoconstriction

7. Serotonin Pharmacological Effects • Respiratory system: bronchoconstriction if asthmatic; stimulation of aortic and carotid chemoreceptors → ↑ RR and minute vol. • GI tract: small intestine very sensitive to serotonin → intense rhythmic contractions due to direct and indirect (ganglia in wall) effects. Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally).

8. Serotonin Pharmacological Effects -2 • Cardiovascular system: Multiple direct and indirect effects: • Direct vasoconstriction (large arteries) and indirect vasodilation (NO and PGI2 – mediated) • Heart: direct inotropic and chronotropic effects • Reflex mechanisms due to change in BP • Stimulation of sensory nerve endings in baroreceptors and in vagal afferents in coronary circulation (Bezold Jarrisch reflex) → bradycardia and hypotension

9. Serotonin in the Central Nervous System • Pain perception • Sleep/Wakefulness • Various behaviors normal/abnormal: depression, schizophrenia, obsessive compulsive behavior, etc. • Neuroendocrine regulation – controls hypothalamic cells involved in release of several anterior pituitary hormones.

10. Migraine • Clinical Presentations: • Often accompanied by brief aura (visual scotomas, hemianopia) • Severe, throbbing, usually unilateral headache (few hours to a few days in duration) • Migraine Pathophysiology: •  Vasomotor mechanism -- inferred from: • increased temporal artery pulsation magnitude • pain relief (by ergotamine) occurs with decreased artery pulsations • Migraine attack associated with (based on histological studies): • sterile neurogenic perivascular edema • inflammation (clinically effective antimigraine medication reduce perivascular inflammation)

11. Migraine: Drug Treatment • Ergotamine: best results when drug administered prior to the attack (prodromal phase) -- less effective as attack progresses • combined with caffeine: better absorption • potentially severe long-lasting Vasoconstriction. • Dihydroergotamine(IV administration mainly): may be appropriate for intractable migraine • Nonsteroidal antiinflammatory drugs (NSAIDs) • Sumatriptan: alternative to ergotamine for acute migraine treatment; not recommended for patients with coronary vascular disease risk. • formulations: subcutaneous injection, oral, nasal spray • selective serotonin-receptor agonist (short duration of action) • probably more effective than ergotamine for management of acute migraine attacks (relief: 10 to 15 minutes following nasal spray)

12. Migraine: Prophylaxis •  Methysergide • effective in about 60% of patients • NOT effective in treating an active migraine attack or even preventing an impending attack. • Methysergide toxicity: retroperitoneal fibroplasia, subendocardial fibrosis. Recommend 3-4 week drug holiday every six months • Propranolol - Most common for continuous prophylaxis • best established drug for migraine attack prevention. • Amitriptyline (TCA) • most frequently used among the tricyclic antidepressants • Valproic acid (Antiepileptic) • effective in decreasing migraine frequency. • Nonsteroidal antiinflammatory drugs(NSAIDs) • used for attack prevention and aborting acute attack

13. Serotonin in Migraine • Neurogenic vs. Vascular theories • Several drugs that modulate the serotonin system are effective in migraine: • Cyproheptadine/methysergide - prophylaxis • Sumatriptan, ergotamine - acute • MAO inhibitors and TCA – both • Caffeine (↑ cAMP?) • Reserpine worsens migraine

14. PAIN Unknown Trigger Activation antidromic Cortex Orthodromic conduction Thalamus Trigeminal neuron Blood Vessel autonomic nausea Mast cell Inhibitory receptor (5-HT1D) Trigem. Nucleus caudalis

15. Serotonin Agonists • Sumatriptan: 5-HT1D agonist; contraindicated in patients with angina • Fluoxetine: Selective serotonin uptake inhibitors for depression and other indications • Buspirone: 5-HT1A agonist for anxiety • Cisapride: 5-HT4 agonist to ↑ GI motility and decrease G-E reflux (Removed from US market due to fatal arrhythmias) • LSD: 5HT1A – hallucinogen • Ergot alkaloids: 5-HT1 and 2 and other receptors

16. Serotonin Antagonists • Methysergide and Cyproheptadine. 5HT2 antagonists. In carcinoid, migraine. • Ketanserin: 5HT2 and Alpha antagonist – used as antihypertensive. • Ondansetron: 5-HT3 antagonist for chemotherapy induced nausea and vomiting • Clozapine: 5HT2A/2C antagonist: for schizophrenia.