This document summarizes information about serotonin and histamine, including their biosynthesis, pharmacological effects, mechanisms of action, and examples of agonists and antagonists. Serotonin is produced in the gastrointestinal tract and central nervous system. It has diverse effects, including acting as a neurotransmitter, regulating cardiovascular and gastrointestinal functions, and mediating platelet aggregation. Histamine acts through H1, H2, and H3 receptors and is involved in allergic responses. Examples are given of several drugs that act as serotonin or histamine receptor agonists or antagonists for conditions like migraine, depression, anxiety, motion sickness, and allergy treatment.

4. 5-Hydroxytryptamine (5-HT), serotonin (Page, 1976) 1. endogenous monoamine 2. central neurotransmitter 3. local (autacoid) action in various tissues Occurrence and distribution Mammalian: (1) about 90% of serotonin produced by enterochromaffin cells in intestine (Erspamer, 1930s) (2) 8% in platelet (uptake system, transporter) (3) 2% in CNS (serotonergic neurons, rostral raphe nuclei), pineal gland, hypothalamus

5. Serotonin GI Psycho. CV Haemo. & Thromb. (Carcinoid tumor)

7. 5-HT4 + -CNS- -GI- Prokinetic (fast) -CNS- Serotonin (5-HT) MAO

8. Hybrid-like, multiple actions

9. Pharmacological effects Cardiovascular system 1. Vasoconstraction (5-HT2A R.), arteriolar dilation (5-HT1 R.),  peripheral adrenergic neurotransmission 2. Triphasic change in blood pressure (1) a transient decrease (reflex stimulation of chemoreceptors within the coronary arteries) (Bezold- Jarisch reflex) (2) a period of hypertension that lasts several minutes (direct constraction of blood vessels of splanchnic and renal vascular beds) (3) a prolonged period of lowered pressure (vasodilation of vessels in specific vascular beds) (ex. Skeletsl muscle) 3. heart: positive inotropic and chronotropic effect (5-HT1)

11. Platelet 1. 5-HT2A produces a weak platelet aggregation, but with adhesive factor (collagen) -> 5-HT can amplify the platelet aggregation reaction and speed clot formation GI tract 1. direct stimulation of intestinal muscle 2. indirect stimulation through excitation of ganalion cells within the intestinal wall -> diarrhea and abdominal pain 3. Cisapride (5-HT4 receptor agonist) ->  propulsive motor activity of stomach and small, large intestine -> treatment of motility disorder Airway bronchial smooth muscle cell constriction

12. CNS 1. stimulate afferent nerve ending, ganalion cells -> pain perception, behavior, body temperature 2.  synaptic transmission -> antidepressant drugs 3. 5-HT1 receptors on adrenergic nerve terminal ->  NE release 4. 5-HT3 receptor located on sensory neuron mediate a depolarizing response -> pain and itching

13. Mechanism of action ketanserin Receptor mechanism Response agonist antagonist 5-HT1A -AC Presynaptic autoreceptor which inhibt neurotransmitter release in doral raphe, hippocampus and cerebral cortex. Postsynaptic receptors at several sites including hippocampus Ergotamine Buspirone 5-HT1C PI turnover Central neuronal depolarizing -- Mianserin Ketanserine 5-HT1D - AC Vasoconstriction in some cranial vascular beds, e.g. carotid artery, pial and dural vessels. Inhibitory presynaptic autoreceptors (which reduce 5-HT release) Sumatriptan 5-HT2 PI turnover Platelet aggregation, vasoconstriction, bronchoconstriction, poatsynaptic receptors mediate central and peripheral neuronal depolarization -- Methysergide Pizotifen mianserin 5-HT3 Ion channel Central and peripheral neuronal depolarization, vomiting via sensory nerve terminals of the vagus -- ondansetron

16. 5-HT agonists and antagonists Ergot alkaloids (Ergotamine, dihydroergotamine, bromociptine, ergonovine, methylergonovine, methysergide ) (1) from Secale cornutum (ergot), the sclerotium of fungus ( Claviceps purpurea ) parasitizing rye (2) contain lysergic acid (3) partial 5-HT, dopaminergic and  -adrenergic receptor agonists (St Anthony’s fire) (4) uterus and vascular smooth contraction (5) prevent migraine headache

19. CNS

21. Methysergide 1. a congener of methylergonovine and LSD 2.  vasoconstrictor and inhibit 5-HT2 receptor and  - adrnergic block 3. prevent migraine headache, but not effective in treatment of established migraine 4. rebound headaches may occur when the drug is withdraw 5. side effect: nausea, dizziness, insomnia, behavioral changes Cyproheptadine 1. H1, 5-HT2A receptor antagonist 2. used to relieve itiching of skin, intestinal hypermotility of carcinoid syndrom 3. side effect: antihistamine-like effect

22. Ketanserin 1.(selective) 5-HT2 antagonist 2. Vasodilation (  1-antagonist), antihypertension Fluoxetine 1. second-line antidepressant (atypical) 2. Block 5-HT reuptake in serotonergic neuron Buspirone 1. anxiolytic drug 2. A partial central 5-HT1A agonist Ondansetron 1. chemotherapy-induced emesis/vomiting 2. Block 5-HT3 receptor 3. 5-HT -> 5-HT3 receptor (chemoreceptor trizzer zone) -> vomting center -> vomting

24. , H4

33. Mechanism of histamine H1 receptor: phosphoinositol-phospholipase C (PI-PLC)->↑Ca 2+ , DAG H2 receptor: activate adenylyl cyclase->↑cAMP H3 receptor: inhibit adenylyl cyclase->↓cAMP

35. H1 antagonists Pharmacology properties 1. Antiallergic action (perennial allergic rhinitis, conjunctivitis, itching) 2. Sediation (drug pass BBB and inhibit central H1) 3. Antimotion sickness (antimuscarinic action) 4. Antiemetic action (inhibit dopamine D2) 5. Antiparkinsonism (antimuscarinic action) 6. Local anesthetic action (inhibit sodium channel in excitable membrane)