IndoleaminesIndoleamines

Lisham AshrafiounLisham Ashrafioun

Michele San GeorgeMichele San George

MelatoninMelatonin

vivo.colostate.edu

MelatoninMelatonin

Receptors (ML1A)Receptors (ML1A) CNS locationsCNS locations

SCN (biological clock)SCN (biological clock) Anterior pituitary (seasonal breeding) Anterior pituitary (seasonal breeding)

PNS locationsPNS locations Retina - circadian and reproductive responsesRetina - circadian and reproductive responses Cardiovascular system - caudal artery that Cardiovascular system - caudal artery that

potentiates NE-induced contractionpotentiates NE-induced contraction Reproductive system – ovaries Reproductive system – ovaries Immune system – T cellsImmune system – T cells Kidneys – Na retentionKidneys – Na retention GI Tract – relaxes smooth muscles (melatonin-5-HT GI Tract – relaxes smooth muscles (melatonin-5-HT

feedback)feedback)

SerotoninSerotonin

5-Hydroxytryptamine (5-HT)5-Hydroxytryptamine (5-HT)

SynthesisSynthesisTryptophan Tryptophan

Hydroxylase 5-Hydroxytrophan (5-HTP)

Amino AcidDecarboxylase5-Hydroxytryptamine (5-HT)

MetabolismMetabolism

5-HT 5-HIAAMonoamineOxidase

5-HIAA: 5-Hydroxy indole amine acid

Inactivation- 5HT reuptakeInactivation- 5HT reuptake

Distribution(PNS)Distribution(PNS)

Majority released from gutMajority released from gut Responsible for smooth muscle contractionsResponsible for smooth muscle contractions Release stimulated by food intakeRelease stimulated by food intake Inhibits release of gastric acidInhibits release of gastric acid Softens stoolSoftens stool

Cardiovascular system – Cardiovascular system – vasoconstrictor/vasodilator of vesselsvasoconstrictor/vasodilator of vessels BonchioconstrictionBonchioconstriction

Uterine contractionsUterine contractions

Distribution: rodentDistribution: rodent

(Cooper, Bloom, Roth, 2003)

receptor 5HT1 5HT2 5HT3 5HT4 5ht5 5ht6

5HT7

subtype 5HT1A, 5HT1B, 5HT1D, 5ht1E, 5HT1F

5HT2A, 5HT2B, 5HT2C  

 

5HT3A, 5HT3B

  5ht1A, 5ht1B

   

major signaling pathway

cAMP↓

IP3 ion channel

cAMP cAMP? cAMP cAMP

 

5HT Receptors5HT Receptors

A few words aboutA few words about signalsignal transductiontransduction

mechanisms…mechanisms…

4 Families of Receptors4 Families of Receptors

Channel linked (Ionotropic)Channel linked (Ionotropic) G-protein coupled G-protein coupled

(Metabotropic)(Metabotropic) Kinase- linked (enzymatic)Kinase- linked (enzymatic) Intracellular (gene transcription)Intracellular (gene transcription)

Ionotropic receptorsIonotropic receptors

G-Protein coupled receptorsG-Protein coupled receptors

The Major G ProteinsThe Major G Proteins

GGss Stimulatory- Activates Ca Stimulatory- Activates Ca channels, activates adenylyl cyclasechannels, activates adenylyl cyclase

GGii Inhibitory- Activates K channels, Inhibitory- Activates K channels, inhibits adenylyl cyclaseinhibits adenylyl cyclase

GGqq – Activates phospholipase C– Activates phospholipase C GGoo - Inhibits Ca channels - Inhibits Ca channels GG12/1312/13 – Diverse ion transporter – Diverse ion transporter

interactionsinteractions

Second Messengers- Second Messengers- Adenylyl CyclaseAdenylyl Cyclase

                                                                            

              

http://www.endocrinesurgeon.co.uk

Second Messenger- Second Messenger- Phospholipase CPhospholipase C

http://www.endocrinesurgeon.co.uk

5HT5HT1A 1A receptorreceptor

CNSforum.com

5HT5HT1A Partial Agonist mechanism1A Partial Agonist mechanism

5HT5HT1A 1A Antagonist Antagonist mechanismmechanism

5HT5HT2 receptor mechanism2 receptor mechanism

5HT5HT2 2 Antagonist Antagonist mechanismsmechanisms

The Swiss army knife of The Swiss army knife of NeurotransmittersNeurotransmitters

DepressionDepression AnxietyAnxiety Social phobiaSocial phobia SchizophreniaSchizophrenia Obsessive-Obsessive-

compulsivecompulsive Panic disorderPanic disorder

MigraineMigraine HypertensionHypertension Pulmonary Pulmonary

hypertensionhypertension Eating disordersEating disorders Vomiting Vomiting Irritable bowel Irritable bowel

syndromesyndrome

Serotenergic DrugsSerotenergic Drugs 5HT5HT1A 1A Buspirone, ipsapirone treat Buspirone, ipsapirone treat

anxiety, depression (partial agonist)anxiety, depression (partial agonist)

5HT5HT1D 1D Sumatriptan, treat migraine Sumatriptan, treat migraine (partial agonist)(partial agonist)

5HT5HT2A/2C 2A/2C methysergide, trazodone, methysergide, trazodone, risperidone, ketanserin treat migraine, risperidone, ketanserin treat migraine, depression, schizophrenia (antagonist)depression, schizophrenia (antagonist)

Drugs continued…Drugs continued…

5HT5HT3 3 Ondansetron treat chemotherapy- Ondansetron treat chemotherapy- induced emesis (antagonist)induced emesis (antagonist)

5HT5HT4 4 Cisapride treat GI disorders Cisapride treat GI disorders (agonist)(agonist)

5HT transporter SSRIs (Fluoxetine, 5HT transporter SSRIs (Fluoxetine, sertraline) treat depression, OCD, panic sertraline) treat depression, OCD, panic disorder, social phobia, post traumatic disorder, social phobia, post traumatic stress disorder (inhibitor) stress disorder (inhibitor)

AntidepressantsAntidepressants

Decreased amounts and impaired Decreased amounts and impaired function of 5-HT associated with function of 5-HT associated with aggression, depression and other aggression, depression and other forms of antisocial behaviorforms of antisocial behavior

Antidepressants attempt to increase Antidepressants attempt to increase 5-HT levels5-HT levels

Serotonin SyndromeSerotonin Syndrome

Toxic, potentially fatal effectsToxic, potentially fatal effects require a combination of serotonergic require a combination of serotonergic

agents, such as an SSRI with an MAOI.agents, such as an SSRI with an MAOI. Symptoms: euphoria, drowsiness, sustained Symptoms: euphoria, drowsiness, sustained

rapid eye movement, overreaction of rapid eye movement, overreaction of reflexes, rapid muscle contraction,abnormal reflexes, rapid muscle contraction,abnormal movements of the foot, drunk, dizzy movements of the foot, drunk, dizzy feeling,high body temperature, shivering , feeling,high body temperature, shivering , diarrhea ,loss of consciousness, deathdiarrhea ,loss of consciousness, death

TreatmentTreatment

suspected agents should be discontinuedsuspected agents should be discontinued OTC drugs containing ingredients known to OTC drugs containing ingredients known to

increase serotonin levels, such as increase serotonin levels, such as dextromethorphan, pseudoephedrine or dextromethorphan, pseudoephedrine or phenylpropanolamine, also should be phenylpropanolamine, also should be discontinued. discontinued.

Benzodiazepines for mild to moderate casesBenzodiazepines for mild to moderate cases

Cyproheptadine, Methysergide, and Propranolol Cyproheptadine, Methysergide, and Propranolol for severe casesfor severe cases

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

go togethergo together LSDLSD

Non-selective 5HT agonist/partial agonistNon-selective 5HT agonist/partial agonist Ergot derivativeErgot derivative Mimics 5HT at 5HTMimics 5HT at 5HT1A1A autoreceptors on autoreceptors on

raphe cell bodies, slows firing rate of raphe cell bodies, slows firing rate of serotonergic neuronsserotonergic neurons

Current theories focus on glutamate Current theories focus on glutamate release in thalamocortical terminals, release in thalamocortical terminals, causing dissociation between sensory causing dissociation between sensory relay and cortical outputrelay and cortical output

Hallucinogens and drug Hallucinogens and drug discrimination trialsdiscrimination trials

Animal model thought to reflect Animal model thought to reflect subjective effectssubjective effects

Mediated by activation of 5HTMediated by activation of 5HT2A2A receptorsreceptors

Acts as partial or full agonist at 5HTActs as partial or full agonist at 5HT2A 2A

and 5HTand 5HT2C 2C receptorsreceptors Phenethylamine derivatives (psilocybin) Phenethylamine derivatives (psilocybin)

are selective 5HTare selective 5HT2A/2C 2A/2C agonistsagonists

Human StudiesHuman Studies

Psilocybin and PET imaging studies- Psilocybin and PET imaging studies- pattern resembles brain activation in pattern resembles brain activation in schizophrenic patientsschizophrenic patients

Action of psilocybin is blocked by Action of psilocybin is blocked by pretreatment with 5HTpretreatment with 5HT2A/2C 2A/2C

antagonistsantagonists

Yeah rub Vaseline on my Yeah rub Vaseline on my eyelids – 5-HT & MDMAeyelids – 5-HT & MDMA

MDMA causes an increased release MDMA causes an increased release of 5-HT and blocks reuptakeof 5-HT and blocks reuptake

High affinity for SERT High affinity for SERT Effects fine axonsEffects fine axons Responsible for temperature Responsible for temperature

increasesincreases

Receptor OverviewReceptor Overview

5HT5HT2 2 subtypessubtypes