Indoleamines Lisham Ashrafioun Michele San George

vivo.colostate.edu

Melatonin

Melatonin  Receptors (ML1A)  CNS locations   SCN (biological clock) Anterior pituitary (seasonal breeding)  PNS locations    Retina - circadian and reproductive responses Cardiovascular system - caudal artery that potentiates NE induced contraction Reproductive system – ovaries    Immune system – T cells Kidneys – Na retention GI Tract – relaxes smooth muscles (melatonin-5-HT feedback)

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 5HT3 5HT4 5ht5

receptor

5HT1 5HT2 5ht6 5HT7

subtype major signaling pathway

5HT1 5HT1 D, 5HT2A, A, 5HT1 5HT2B, 5HT2C B, 5HT3A, 5HT3B 5ht1E, 5HT1 F cAMP ↓ IP3  ion channel cAMP  5ht1A, 5ht1B 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     

G s Stimulatory- Activates Ca channels, activates adenylyl cyclase G i Inhibitory- Activates K channels, inhibits adenylyl cyclase G q – Activates phospholipase C G

o - Inhibits Ca channels

G

12/13 – Diverse ion transporter interactions

 Second Messengers Adenylyl Cyclase http://www.endocrinesurgeon.co.uk

 Second Messenger Phospholipase C http://www.endocrinesurgeon.co.uk

5HT 1A receptor CNSforum.com

5HT 1A Partial Agonist mechanism

5HT 1A Antagonist mechanism

5HT 2 receptor mechanism

5HT 2 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  5HT 1A Buspirone, ipsapirone treat anxiety, depression (partial agonist)  5HT 1D Sumatriptan, treat migraine (partial agonist)  5HT 2A/2C methysergide, trazodone, risperidone, ketanserin treat migraine, depression, schizophrenia (antagonist)

Drugs continued…    5HT 3 Ondansetron treat chemotherapy induced emesis (antagonist) 5HT 4 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 5HT 1A 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 5HT 2A receptors Acts as partial or full agonist at 5HT 2A and 5HT 2C receptors Phenethylamine derivatives (psilocybin) are selective 5HT 2A/2C agonists

Human Studies   Psilocybin and PET imaging studies pattern resembles brain activation in schizophrenic patients Action of psilocybin is blocked by pretreatment with 5HT 2A/2C antagonists

Yeah rub Vaseline on my eyelids – 5-HT & MDMA     MDMA causes an increased release of 5 HT and blocks reuptake High affinity for SERT Effects fine axons Responsible for temperature increases

Receptor Overview

5HT 2 subtypes