Indoleamines

Lisham Ashrafioun

Michele San George

Melatonin

vivo.colostate.edu

Melatonin

Receptors (ML1A)

CNS locations

SCN (biological clock) Anterior pituitary (seasonal breeding) Retina - circadian and reproductive responses Cardiovascular system - caudal artery that potentiates NEinduced contraction Reproductive system ovaries Immune system T cells Kidneys Na retention GI Tract relaxes smooth muscles (melatonin-5-HT feedback)

PNS locations

Serotonin
5-Hydroxytryptamine (5-HT)

Synthesis
Tryptophan
Tryptophan Hydroxylase

5-Hydroxytrophan (5-HTP)

5-Hydroxytryptamine (5-HT)

Amino Acid Decarboxylase

Metabolism

5-HT

Monoamine Oxidase

5-HIAA

5-HIAA: 5-Hydroxy indole amine acid

Inactivation- 5HT reuptake

Distribution(PNS)

Majority released from gut

Responsible for smooth muscle contractions Release stimulated by food intake Inhibits release of gastric acid Softens stool

Cardiovascular system vasoconstrictor/vasodilator of vessels

Bonchioconstriction

Uterine contractions

Distribution: rodent

(Cooper, Bloom, Roth, 2003)

5HT Receptors
receptor 5HT1 5HT2 5HT3 5HT4 5ht5 5ht6 5HT7

subtype

5HT1 5HT2A, A, 5HT2B, 5HT1 5HT2C B, 5HT1 D, 5ht1E, 5HT1 F

IP3

5HT3A, 5HT3B

5ht1A, 5ht1B

major cAMP signaling pathway

ion channel

cAMP

cAMP? cAMP

cAMP

A few words about signal transduction mechanisms

4 Families of Receptors
Channel linked (Ionotropic) G-protein coupled (Metabotropic)

Kinase- linked (enzymatic) Intracellular (gene transcription)

Ionotropic receptors

G-Protein coupled receptors

The Major G Proteins

Gs Stimulatory- Activates Ca channels,

activates adenylyl cyclase

Gi Inhibitory- Activates K channels,

inhibits adenylyl cyclase

Gq Activates phospholipase C
Go - Inhibits Ca channels G12/13 Diverse ion transporter interactions

Second MessengersAdenylyl Cyclase

http://www.endocrinesurgeon.co.uk

Second MessengerPhospholipase C

http://www.endocrinesurgeon.co.uk

5HT1A receptor

CNSforum.com

5HT1A Partial Agonist mechanism

5HT1A Antagonist mechanism

5HT2 receptor mechanism

5HT2 Antagonist mechanisms

The Swiss army knife of Neurotransmitters

Depression Anxiety Social phobia Schizophrenia Obsessive-compulsive Panic disorder

Migraine Hypertension Pulmonary hypertension Eating disorders Vomiting Irritable bowel syndrome

Serotenergic Drugs

5HT1A Buspirone, ipsapirone treat anxiety, depression (partial agonist) 5HT1D Sumatriptan, treat migraine (partial agonist)

5HT2A/2C methysergide, trazodone, risperidone, ketanserin treat migraine, depression, schizophrenia (antagonist)

Drugs continued

5HT3 Ondansetron treat chemotherapyinduced emesis (antagonist) 5HT4 Cisapride treat GI disorders (agonist) 5HT transporter SSRIs (Fluoxetine, sertraline) treat depression, OCD, panic disorder, social phobia, post traumatic stress disorder (inhibitor)

Antidepressants

Decreased amounts and impaired function of 5-HT associated with aggression, depression and other forms of antisocial behavior Antidepressants attempt to increase 5-HT levels

Serotonin Syndrome

Toxic, potentially fatal effects require a combination of serotonergic agents, such as an SSRI with an MAOI. Symptoms: euphoria, drowsiness, sustained rapid eye movement, overreaction of reflexes, rapid muscle contraction,abnormal movements of the foot, drunk, dizzy feeling,high body temperature, shivering , diarrhea ,loss of consciousness, death

Treatment

suspected agents should be discontinued OTC drugs containing ingredients known to increase serotonin levels, such as dextromethorphan, pseudoephedrine or phenylpropanolamine, also should be discontinued. Benzodiazepines for mild to moderate cases
Cyproheptadine, Methysergide, and Propranolol for severe cases

Oh man I just saw God and he was playing a mandolin and he told me to watch Fear and Loathing in Las Vegas while listening to The Doors self-titled album and dude they totally go together LSD

Non-selective 5HT agonist/partial agonist Ergot derivative Mimics 5HT at 5HT1A autoreceptors on raphe cell bodies, slows firing rate of serotonergic neurons Current theories focus on glutamate release in thalamocortical terminals, causing dissociation between sensory relay and cortical output

Hallucinogens and drug discrimination trials

Animal model thought to reflect subjective effects Mediated by activation of 5HT2A receptors Acts as partial or full agonist at 5HT2A and 5HT2C receptors Phenethylamine derivatives (psilocybin) are selective 5HT2A/2C agonists

Human Studies

Psilocybin and PET imaging studiespattern resembles brain activation in schizophrenic patients Action of psilocybin is blocked by pretreatment with 5HT2A/2C antagonists

Yeah rub Vaseline on my eyelids 5-HT & MDMA

MDMA causes an increased release of 5HT and blocks reuptake High affinity for SERT Effects fine axons Responsible for temperature increases

Receptor Overview

5HT2 subtypes