Serotonin : Serotonin Dr. P. K. Verma
Division of Pharmacology And Toxicology
Faculty of Veterinary Sciences and Animal Husbandry
R. S. Pura Jammu Serotonin : Serotonin Page & coworkers name serotonin to an unknown vasoconstrictor substance in serum in 1976.
Chemically - 5- hydroxytryptamine (5-HT)
Widely distributed in mammals, plants and insects
Chromaffin cells of GIT (>90%),
Specific region of brain & platelets.
It is also present in plant like tomato, banana & pineapple lower animals (mollusks, arthropods, snake and bee venom/sting) Regulatory role of serotonin….. : Regulatory role of serotonin….. Primary involve in regulation of tone & motility of gastrointestinal tract
Act as precursor molecule for melatonin
Its deficiency causes depression & excess cause excitation.
Involved in hemostasis (platelets),
Carcinoid syndrome (tumor of serotonin producing cells) Role in brain…. : Act as a neurotransmitter in tryptaminergic nerves (raphe nucleus in the brainstem)
Regulate appetite, body temperature etc.
Pain perception, e.g. Headache, Migraine
Various behaviors/mood normal/abnormal, depression, schizophrenia, etc.
Neuro-endocrine regulation – controls release of several anterior pituitary hormones, prolactin. Role in brain…. Slide 5: Synthesis and metabolism N 5-Hydroxytryptophan 5-Hydroxytryptamine Tryptophan hydroxylase 5-OH Tryptophan
decarboxylase Rate limiting step Carrier mediated uptake…… : Carrier mediated uptake…… In addition to metabolism carrier mediated uptake take place to terminate the action
5-HT transporter proteins are present on outer membrane of platelets and serotonergic neurons.
Due to deficiency of tryptophan hydroxylase 5-HT can’t synthesized in platelets but it is taken up from the circulation by active transport through serotonin transporter proteins. Drugs affecting on tryptaminergic system : Drugs affecting on tryptaminergic system 5-HT Precursor – ↑Tryptophan in diet ↑ 5-HT production
Synthesis inhibitors – p-chloro-phenylalanine (PCPA) inhibit tryptophan hydroxylase - ↓ 5-HT production
Storage inhibitors – (selectively release the 5-HT) Fenfluramine, dexfenfluramine
Uptake inhibitor – selective serotonin reuptake inhibitors (SSRI). Fluoxetine, Paroxetine, Slide 9: Neuronal degradation – 5-6 di-hydroxytryptamine selectively destroys tryptaminergic neurons in brain.
Inhibit metabolism: MAO inhibitors Clorgyline, Selegiline
Promote release: p-chloroamphetamine - then depletes the storage Mechanism of action : Mechanism of action Interaction with tryptaminergic receptors
These receptors are of seven types (5-HT1, 5-HT2 ,….5-HT7)
5-HT1 and 5-HT2 have (A - D) subtypes
5-HT1A 5-HT1B…. 5-HT1D
5-HT2A 5-HT2B…. 5-HT2D Slide 12: Pharmacological Effects on different system Cardiovascular system : Multiple direct and indirect effects:
Direct vasoconstriction (large arteries) and
Indirect vasodilatation in small blood vessels due to
Partially by release of relaxing factors (NO and PGI2–mediators)
partially by inhibiting EN/NE release from sympathetic nerve terminals.
Heart: direct ionotropic and chronotropic effects
Reflex mechanisms due to stimulation of sensory nerve endings in baro-receptors, chemo-receptors and in vagal afferents in coronary circulation (Bezold Jarrisch reflex) → Bradycardia and hypotension Cardiovascular system Triphasic response : Triphasic response A rapid intravenous injection of 5-HT
Initial rise in systemic arterial blood pressure
Short period of pressor effect
Prolong fall in systemic blood pressure due to vasodilatation Gastrointestinal tract : Gastrointestinal tract Entero-chromaffin cells in the mucosa main 5-HT in body
↑ GIT motility
partly through direct effect on the smooth muscle cells (5-HT2 receptor)
partly as a result of indirect excitatory effect on enteric neurons (5-HT3 & 4 receptors).
Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally) on 5-HT receptors.
5-HT inhibit gastric acid and pepsin, secretion however increase mucus production thus it has ulcer protective property. Respiratory system : Respiratory system Bronchoconstriction stimulation of aortic and carotid chemo-receptors result increase in respiration rate and minute volume.
It produces vasoconstriction in renal and splanchic beds, placental, uterine, umbilical, and to a lesser degree to pulmonary vessels while vasodilatation of skeletal muscle beds. Platelets : Platelets The main function of is to prevent leakage
Platelets have 5-HT2 receptors in the membrane on interaction
it increases the platelet aggregation and
vasoconstriction to leakage site thereby promotes hemostasis. Brain : Brain Neurotransmitter in serotonergic neuron (raphe nuclei, pons & medulla)
These neurons mainly regulate appetite, mood, sleep body temperature, thought, pain perception, vomiting & behaviors (normal and abnormal).
5-HT poorly cross blood brain barrier however direct injection in brain produces sleepiness, change in body temperature, vomition & appetite.
Serotonin stimulates adrenal gland (autonomic ganglia) for release catecholamine. Serotonin receptor Agonists : Serotonin receptor Agonists Sumatriptan: 5-HT1D agonist; contraindicated in patients with angina
Buspirone: 5-HT1A agonist for anxiety
Cisapride: 5-HT4 agonist to ↑ GI motility and decrease GIT reflux
5HT3 receptor agonists – Painful stimulation (Experimental purpose) Antagonists of serotonin : Antagonists of serotonin Cyproheptadine: migraine, appetite stimulant in young animals and control skin allergies (In carcinoid)
Katanserin: used as antihypertensive
Methysergide: - In carcinoid, migraine.
Clozapine: for schizophrenia.
Metoclopramide, Ondansetron and Granisetron are currently available as anti-emetic for chemotherapeutic induced nausea and vomiting (5-HT3 antagonists). Ergot Alkaloids and derivatives : Ergot Alkaloids and derivatives Ergot alkaloids ----toxic effects
First isolated by Dale & Barger in 1906 from fungus Claviceps purpurea ---- on rye and other grains
They have long been recognized as abortifacients and poisonings produced an intense burning sensation & gangrenous condition in the limbs as a result of persistent peripheral vasoconstriction. Classification of ergot alkaloids : Classification of ergot alkaloids Natural – Derivatives of the tetra-cyclic compounds (lysergic acid).
Amine alkaloids – Ergometrine
Amino acid alkaloids - Ergotamine, Ergotoxine
Semi-synthetic – Bromocriptine, Methysergide, Dihydro-ergotamine
Synthetic – (non lysergic acid derivative) Metergotine Slide 23: The interaction of ergot alkaloids with serotonergic receptor systems is variable and complex, with some compounds acting as partial agonists in some tissues and as antagonists in others.
Interaction with other receptor types such as alpha adrenergic and dopaminergic can contribute to both therapeutic and adverse effects of ergot. Ergotamine and Dihydro-ergotamine : Ergotamine and Dihydro-ergotamine Have high affinity but poor selectivity for antagonizing 5-HT1 receptors.
Also block the reuptake of NE which contributes to vasoconstrictor response.
Ergotamine is can be administered orally, sublingually, and nasally, but is best absorbed rectally.
Dihydro-ergotamine stimulates the chemoreceptor trigger zone (CTZ) and may require an anti-emetic.
Methysergide a semi-synthetic ergot alkaloid is a 5-HT2 antagonist with greater potency than ergotamine and dihydro-ergotamine that is used for migraine prophylaxis. Ergot poisoning : Ergot poisoning Acute poisoning - vomiting, diarrhea, thirst, tingling, itching, coldness of the skin, weak pulse, confusion, unconsciousness
Chronic poisoning - cold, numb extremities, circulatory disturbances, gangrene, headache, nausea, vomiting, diarrhea, confusion, drowsiness Slide 26: THANKS….