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.

N C N CNH 2 COOH NH 2 OH N CNH 2 OH H Tryptophan5-Hydroxytryptophan 5-Hydroxytryptamine N CCOOH 5-OH Indole Acetaldehyde 5-Hydroxy Indole Acetic Acid Tryptophan hydroxylase 5-OH Tryptophan decarboxylase MAO Aldehyde dehydrogenase (Rate limiting) In diet. Active CNS transport

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.

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

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.

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

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).

Cardiovascular system: Multiple direct and indirect effects: 1.Direct vasoconstriction (large arteries) and indirect vasodilation (NO and PGI 2 – mediated) 2.Heart: direct inotropic and chronotropic effects 3.Reflex mechanisms due to change in BP 4.Stimulation of sensory nerve endings in baroreceptors and in vagal afferents in coronary circulation (Bezold Jarrisch reflex) → bradycardia and hypotension Serotonin Pharmacological Effects -2

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. Serotonin in the Central Nervous System

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)

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)

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

Serotonin in Migraine Neurogenic vs. Vascular theories Several drugs that modulate the serotonin system are effective in migraine: 1.Cyproheptadine/methysergide - prophylaxis 2.Sumatriptan, ergotamine - acute 3.MAO inhibitors and TCA – both 4.Caffeine (↑ cAMP?) 5.Reserpine worsens migraine

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

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

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.