SEROTONIN

And its role in psychiatry

Aditya Agrawal,
First year, Junior resident
Department of Psychiatry,
K.G.M.U.,
Lucknow
CONTENTS

 Introduction
 Metabolism
 Physiological role
 Pathways in the brain
 Receptors
 Role in diseases
 Drugs
INTRODUCTION
INTRODUCTION

 Monoamine neurotransmitter
 Synthesized from tryptophan
 80% is found in gastrointestinal system , 1-2% only in brain
 Only one in a million neurons produce serotonin yet it influences
virtually all aspects of CNS function through its neuromodulatory
INTRODUCTION

 14 receptors have been discovered

 Exact role of each receptor still remains elusive
 Maximum density is located in the Raphe Nucleus of the midbrain
METABOLISM
LNAA Insulin SYNTHESIS

Tryptophan in brain

• TPOH – tryptophan • ADCC – Aromatic L AA 5 Hydroxy

Tryptophan
hydroxylase 5 HydroxyDecarboxylase VMAT2 – Vesicular Serotonin in
Tryptamine/ vesicles
• [BH4]
Tryptophan
• [B6] Serotoninmonoamine Transporter

RLS

Ca++
mediated
release
TERMINATION

 Extracellular – MAO A, B
 Reuptake – SERT in presynaptic
 Intracellular
 Reuptake in vesicle
 If High conc. -> MAO B
 End product –
5HIAA – 5 hydroxy Indole Acetic Acid
 low 5HIAA has been associated
with suicide and aggression
https://sapiensoup.com/serotonin
PHYSIOLOGICAL ROLE
In peripheral organs
CARDIORESPIRATORY
GIT

 Max 5HT in GIT (80-

85%)
REPRODUCTIVE SYSTEM
OTHER
PATHWAYS IN THE BRAIN
 Dorsal raphe
RAPHE NUCLEI nucleus
(largest)
Caudal linear
Rostral group
 Max. density of nucleus
serotonergic neurons Median
in the brain raphe
nucleus
 Group of nuclei in the Raphe nuclei
raphe
raphe region of magnus
brainstem nucleus
raphe
Caudal group obscurus
nucleus
raphe
Dingman M. Know Your Brain: Telencephalon. Neuroscientifically Challenged. http://www.neuroscientificallychallenged.com/blog/know-your-brain-
pallidus
telencephalon. Published July 7, 2017
Hornung JP. The human raphe nuclei and the serotonergic system. J Chem Neuroanat. 2003;26(4):331-343. doi:10.1016/j.jchemneu.2003.10.002
nucleus
 Cortex, Dorsal raphe
thalamus, nucleus
(largest)
striatum
Caudal linear
Rostral group
nucleus
Median
raphe Limbic,
nucleus Hippocampus
Raphe nuclei
raphe
Motor, Pain, magnus
ANS nucleus
regulation raphe mood, anxiety,
Caudal group obscurus
Brainstem, cognition,
nucleus
cerebellum feeding,
raphe
spinal cord pallidus sleep – wake cycle
nucleus sexual behavior.
Dingman M. Know Your Brain: Telencephalon. Neuroscientifically Challenged. http://www.neuroscientificallychallenged.com/blog/know-your-brain-telencephalon. Published July 7, 2017
Hornung JP. The human raphe nuclei and the serotonergic system. J Chem Neuroanat. 2003;26(4):331-343. doi:10.1016/j.jchemneu.2003.10.002
Biological psychology
 Fibres from these nuclei extend to the brain through the medial
forebrain bundle and then join all main fibre bundles in the
forebrain.

 Extremely complex to describe, since they include aspects of all

the main pathways in the brain.
  ACN -Nucleus Accumbens,
 CE-Cerebellum ,
 CX -cortex
 HIp -hippocampus
 SN-Substantia Nigra ,
 Pag - periaqueductal grey

Charnay Y, Léger L. Brain serotonergic circuitries. Dialogues Clin Neurosci. 2010;12(4):471-487. doi:10.31887/DCNS.2010.12.4/ycharnay
RECEPTORS
And their mechanisms
RECEPTOR CLASSIFICATION
 7 distinct families of 5HT receptors have been identified (5HT1 to 5HT7).
 14 distinct serotonin receptor subtypes

All of them are G protein coupled except the inotropic 5HT3 receptor.  

Can also be classified as

 Presynaptic
 5HT1A – Somatodendritic autoreceptor
 5HT1B/1D – terminal autoreceptor
 Postsynaptic – rest all
 5HT1A

 Postsynaptic – in PFC Drugs

 Inhibits GLU -> decreases GABA -> increases  Partial agonist –
DA in striatum
 BUSPIRONE – Anti
anxiety
 Presynaptic – in Raphe nucleus  CLOZAPINE,
 Decreases 5HT -> Increases DA in striatum QUETIAPINE,
LURASIDONE,
ARIPIPRAZOLE
Clinical Implication  VORTIOXETINE
 Agonism leads to decreased risk of EPS
 Anti depressant effect
5HT1B/1D

 1B – rats, 1D - humans Drugs

 Agonist – TRIPTANS
 Vasoconstrictive and immunomodulatory
effect

Clinical Implication
 Role in migraine
 ADHD
 Locus coeruleus - Pain pathways
5HT1E & 1F

 Not much studied Drugs

 1F Agonist – TRIPTANS
 1E – high in hippocampus
 Drug target for Alzheimer’s disease

 1F – Trigeminal ganglion, blood vessels

 5HT2A

 Cortex, thalamus, basal ganglia Drugs

 Stimulates GLU -> Increases GABA ->  Hallucinogens – LSD –
Decreases DA in striatum partial / full agonism at
 Increases Prolactin hormone 5HT2A
 Stimulation in cortex– hallucinations  Atypical antipsychotics –
antagonistic at 5HT2A –
Reduced EPS
Clinical Implication  PIMAVANSERIN –
 Antagonism – reduced EPS, hyperprolactinemia Approved for Parkinson
disease psychosis
 Levodopa induced Psychosis – excess
stimulation -> visual hallucination
 5HT2B

 Peripheral > CNS

 Gastric fundus – contraction

Clinical Implication
 Side effects of serotonergic drugs
 GIT
 Agonist – Cardiac valvulopathy
 5HT2C

 Heterogenous – DA, NE regulation Drugs

 Agonism – Suppression of dopamine more in  Agonist –
mesolimbic > striatum  VABACASERIN – ideal
 Antagonism – Increased NE, DA in cortex antipsychotic?
 LORCASERIN – Anti
 Implicated in metabolic side effects of obesity
atypicals
 Antagonist – antidepressant
effect
Clinical Implication  OLANZAPINE, QUETIAPINE
 Antagonism – Antidepressant effect,  FLUOXETINE
metabolic side effects
 5HT3

 Inotropic channel Drugs

 medulla and spinal cord – CTZ – Vomitting  Antagonist –
 Periphery - Pain regulation, CVS reflexes, Enteric  ONDANSETRON –
Vomitting, IBS
 Increase release of NE, Ach, DA, Histamine, 5HT
 Antagonist – antidepressant
effect –
Clinical Implication  MIRTAZAPINE
 VORTIOXETINE
 Chemotherapy induced nausea
 Antagonism – Antidepressant, procognitive
effects
5HT4

 Brain and periphery Drugs

 Agonist –
 CISAPRIDE – prokinetics
 Partial agonist
 TEGASEROD – Rx of
Clinical Implication IBS
 Agonist – Increase GI motility
5HT6
Drugs
 Limbic system and cortex
 Regulate release of neurotropic factors like
BDNF, which regulate long term memory

Clinical Implication
 Antagonist – may improve cognitive
performance in Alzheimer’s
5HT7

 Hippocampus and PFC Drugs

 Involved in control of Circadian Rhythm,  Antagonist
sleep, mood and thermoregulation, (?  LURASIDONE - Rx of Bipolar
cognition) depression

Clinical Implication
 Antagonist – may improve cognition and
elevate mood
ROLE IN DISEASES
DEPRESSION

 Monoamine hypothesis
 Monoamines reduced/ depleted/ dysfunction
 Upregulation of post synaptic receptors
 LOW 5HIAA levels in CSF in suicidal patients
 Lower synaptic 5HT levels
 Higher presynaptic 5HT1A R
 Lower post synaptic 5HT2 R levels
ANXIETY

 5HT in PFC, Amygdala – heightened awareness to threats

 5HT in Dorsal PAG – inhibit flight or fight response
 5HT1A & 5HT2A
OCD

 Dysregulation of serotonin is involved in the symptom

formation of obsessions and compulsions
 Serotonin drugs are more effective than drugs that affect other
neurotransmitter systems.
 Unclear mechanism
SCHIZOPHRENIA

 Serotonergic overdrive occurs in the cerebral cortex, especially

in the anterior cingulate cortex (ACC) and dorsolateral frontal
lobe.
 5HT2A antagonism - > slow progression of disease
PSYCHOSEXUAL DISORDERS

 5HT – Inhibits sexual activity

 Stimulation of 5- HT2C receptors - increases erections and
inhibits ejaculation
 Stimulation of 5-HT1A receptors has the opposite effects like
facilitation of ejaculation and, in some circumstances, inhibition
of erection.

 SSRI induced sexual dysfunction – 50-60 %

EATING DISORDERS

 Anorectic effect of 5HT through 5HT2C

 Bulimia – Emaesis – 5HT3
 SSRI used in treatment
OTHER DISORDERS

 IMPULSE CONTROL DISORDERS - Low levels of 5-HIAA

are associated with violent suicide attempts and impulsive
aggression.

 SUBSTANCE USE DISORDERS – Regulate dopamine

reward pathway, involved in compulsive drug use and
addiction.
DRUGS
To alter serotonin
Frazer A, Hensler JG. Serotonin. In: Siegel GJ, Agranoff BW, Albers RW, et al, editors. Basic neurochemistry. Molecular cellular and medical aspects. 6th ed. Philadelphia: Lippincott Williams &
Wilkins, 1999
Drug class Dug names Effect on 5HT
Atypical antipsychotics CLOZAPINE, OLANZAPINE, 5HT2A antagonist,
RISPERIDONE, QUETIAPINE, Variable action on other
ARIPIPRAZOLE, 5HT receptors
Anti anxiety BUSPIRONE, GEPIRONE, 5HT1A Partial agonist
VILAZODONE
SSRI ESCITALOPRAM, SERT blocker
SERTRALINE, PAROXETINE
FLUOXETINE SERT blocker + 5HT2C
Anatgonist
SNRI VENLAFAXINE, SERT blocker
DESVENLAFAXINE,
DULOXETINE,
MILNACIPRAN
NASSA MIANSERIN, MIRTAZAPINE 5HT2, 5HT3 Antagonist
 Drug class Dug names Effect on 5HT
ANTI-ANXIETY
SPARI VILAZODONE SERT blocker, 5HT1A
partial agonist
SARI TRAZODONE, SERT blocker, 5HT2A &
NEFAZODONE, 2C antagonism
VORTIOXETINE
MAOIs Non selective - MAO inhibitor
ISOCARBOXAZID,
HYDRACARBAZINE,
TRANYLCYPROMINE,
MAO A Inhibitor–
MOCLOBEMIDE,
MAO B Inhibitor –
SELEGILINE, RASAGILINE,
AND SAFINAMIDE
Drug class Drug Names Effect on 5 HT
TCAs AMITRIPTYLINE, IMIPRAMINE, SERT blocker
DESIPRAMINE, NORTRIPTYLINE,
CLOMIPRAMINE,
TRIMIPRAMINE
Antiemetics ONDANSETRON, 5HT3 Antagonist
GRANISETRON, DOLASETRON,
AND PALONOSETRON
Antimigraine – SUMATRIPTAN, NARATRIPTAN, 5HT1B/1D, 5HT1F Agonist
triptans ZOLMITRIPTAN, RIZATRIPTAN,
FROVATRIPTAN, ALMOTRIPTAN
Drug class Dug names Effect on 5HT
Antihistaminic CYPROHEPTADINE 5HT2 antagonist
Ergots ERGOTAMINE 5HT1, 5HT2 Antagonist
Hallucinogens LSD 5HT2 Agonist
Newer drugs AGOMELATINE 5HT2C antagonist
FILBANSERIN 5HT1A agonist, 5HT2A,
2C Antagonist
THANK YOU