SEROTONERGIC SYSTEM

Moderators: Dr. Sharbandh Raj Dr. Swaroopa Chary

Presentator : Dr. T.Ravikanth

Overview Introduction Synthesis. Degradation. Serotonin Receptors. Pathways in Brain. Disorders associated with malfunctioned

Serotonergic System. Drugs affecting on serotonergic System

Serotonin is a monoamine neurotransmitter. extensively in GIT 80 to 90 percent - enterochromaffin cells in the gut,

where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons in

the central nervous system.

Despite the abundance of peripheral serotonin, its inability to cross the BBB necessitates the synthesis of serotonin within the brain.

Serotonin is synthesized from the amino acid tryptophan, which is derived from the diet.

Introduction

Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood.

There, it is actively taken up by blood platelets, which store it.

When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting.

Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing.

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

Bronchioconstriction

Uterine contractions

Serotonin roles Peripheral

Peristalsis Vomiting

Platelet aggregation and haemostasis Inflammatory mediator

Sensitisation of nociceptors

Serotonin roles Central

Control of appetite Sleep

Mood Hallucinations

Stereotyped behaviour

Pain perception Vomiting

SEROTONIN SYNTHESIS AND TERMINATION

N

C

N

C NH2

COOH COOH

NH2

OH

N

C NH2

OH H

Tryptophan 5-Hydroxytryptophan

5-Hydroxytryptamine

N

C COOH

5-OH Indole Acetaldehyde

5-Hydroxy Indole Acetic Acid

Tryptophan hydroxylase

5-OH Tryptophan decarboxylase

MAO

Aldehyde

dehydrogenase

(Rate limiting)

In diet. ActiveCNS transport

B

MAO A or B

(SERT)

Serotonin RECEPTORS

Serotonin receptors

Serotonin Receptors 14 distinct serotonin receptor subtypes

The 5-HT1 receptors = largest subfamily

The most intensively studied of these has been the 5-HT1A receptor.

This subtype is found on both postsynaptic membranes of forebrain neurons primarily in the hippocampus, cortex, and septum and on serotonergic neurons.

It also functions as a somatodendritic autoreceptor.

5HT1A – auto receptors

SOMATODENDRITIC AUTORECEPTOR

5HT1D – auto receptors

TERMINAL AUTORECEPTOR

Receptor

5-HT

1

5-HT 2 5-HT 3 5-HT 4 5-HT 5 5-HT

6

5-HT 7

Subtype

5-HT1A

5-HT

1B 5-HT

1D

5-HT

1E 5-HT 1F

5-HT 2A

5-HT 2B

5-HT 2C   

5-HT 3A

5-HT 3B

     

Major signalin

g pathwa

y

cAMP↓

IP3ion

channel

cAMP cAMP ↓

cAMP cAMP

5-HT Receptors

5–HT5A5–

HT5B

Serotonin receptors 5–HT1

7 trans–membrane domains G protein linked cAMP dependant Anxiolytic and antidepressant Subtypes

5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F

5–HT1A

Limbic system Regulation of emotions

Neocortex Hypothalamus Substantia gelatinosa

Proprioception

5-HT1A Receptor

CNSforum.com

5-HT1A Partial Agonist (Buspirone) Mechanism

5-HT1A Antagonist mechanism

5-HT 1•5-HT1 receptors occur primarily in the brain and cerebral blood vessels (5-HT1D only), where they mediate neural inhibition and vasoconstriction.

•They function mainly as inhibitory presynaptic receptors, linked to inhibition of adenylate cyclase.

•Specific agonists at 5-HT1 receptors include • Sumatriptan (used in migraine therapy)• Buspirone (used in the treatment of anxiety).

•Spiperone and methiothepin are specific antagonists of 5-HT1 receptors.

Serotonin receptors 5–HT2

7 trans–membrane domains G protein linked Phospholipase C dependant Subtypes

5–HT2A, 5–HT2B, 5–HT2C

5-HT2 Receptor Mechanism

5-HT2 Antagonist Mechanism

5–HT2 5–HT2A

Periphery

Contraction of vascular /non–vascular smooth muscle Platelet aggregation Increased capillary permeability

Cognitive process of working memory, a function believed to be impaired in schizophrenia.

Modulation of the release of other neurotransmitters and hormones ACh, Adrenaline, Dopamine, Excitatory amino acids,

Vasopressin

5–HT2

5–HT2A CNS

Motor behaviour Sleep regulation Nociception Neuroexcitation

5-HT3 •5-HT3 receptors occur mainly in the peripheral nervous system, particularly on nociceptive afferent neurones and on autonomic and enteric neurones.

•The effects of these receptors are excitatory, mediated by receptor-coupled ion channels.

•5-HT3 antagonists (eg ondansetron, tropisetron) are used predominantly as anti-emetic drugs.

Other 5-HT receptors 5-HT4 receptors are found in the brain, as

well as peripheral organs like the heart, bladder and gastrointestinal (GI) tract.

stimulating peristalsis. A specific 5-HT4 agonist is

metoclopramide used for treating gastrointestinal disorders.

Little is known about the function and pharmacology of 5-HT5, 5-HT6 and 5-HT7 receptors.

Serotonin Pathways in Brain

AMG, amygdala; CBM, cerebellum; cc, corpus callosum; CP, caudate putamen; CRN, caudal raphe nuclei; CTX, neocortex; DR, dorsal raphe nucleus; HI, hippocampus; HY, hypothalamus; LC, locus ceruleus; MR, median raphe nucleus; NAc, nucleus accumbens; OB, olfactory bulb; SN, substantia nigra; TE, tectum; TH, thalamus; TM, tuberomammillary

nucleus of hypothalamus.

Pathways in Brain Serotonin has both ascending & decending

projections.

Ascending serononergic projections Serotonergic neurons are clustered in midline raphe

nuclei of the midbrain, pons, and medulla  Ascending projections from these nuclei course through the

medial forebrain bundle before diverging to many target regions.

 median raphe nucleus provides the majority of the serotonergic innervation of the limbic system, including the hippocampus and septum,

dorsal raphe nucleus provides the primary innervation of the striatum and thalamus.

Decendng serononergic projection extend down the brainstem, and through the spinal cord.

The caudal raphe serotonergic neurons project to the medulla, cerebellum, and spinal cord.

Serotonergic efferents to the dorsal horn of the spinal cord have been implicated in the suppression of nociceptive pathways.

Function Ascending pathway regulates

Mood, Anxiety, Sleep

Decending pathway regulate the pain sentation.

Disorders associated with malfunctioned Serononergic

Sysyem1. Mood Disorders

2. Anxiety Disorder

3. Schizophrenia

4. ADHD

5. Sexual Disorders

6. Impulse Control Disorder

7. Personality disorders

8. Carcinoid syndrome

Mood Disorders With the huge effect that the selective serotonin reuptake

inhibitors (SSRIs) for example, fluoxetine have made on the treatment of depression, serotonin has become the biogenic amine neurotransmitter most commonly associated with depression.

The identification of multiple serotonin receptor subtypes has also increased the excitement within the research community about the development of even more specific treatments for depression.

Depletion of serotonin may precipitate depression, and some patients with suicidal impulses have low cerebrospinal fluid (CSF) concentrations of serotonin metabolites and low concentrations of serotonin uptake sites on platelets.

Anxiety and Serotonin Different types of acute stress result in increased 5-HT

turnover in the prefrontal cortex, nucleus accumbens, amygdala, and lateral hypothalamus.

5-HT release may have anxiogenic and anxiolytic effects, depending on the region of the forebrain involved and the receptor subtype activated. Anxiogenic effects are mediated via 5-HT2A receptor, stimulation of 5-HT1A receptors is anxiolytic.

serotonergic antidepressants have therapeutic effects in some anxiety disorders for example, clomipramine (Anafranil) in OCD.

The effectiveness of buspirone (BuSpar), a serotonin 5-HT1A receptor agonist, in the treatment of anxiety disorders

Schizophrenia Current hypotheses posit serotonin

excess as a cause of both positive and negative symptoms in schizophrenia.

The robust serotonin antagonist activity of clozapine and other second-generation antipsychotics, coupled with the effectiveness of clozapine to decrease positive symptoms in chronic patients has contributed to the validity of this proposition. 

ADHD There is weak evidence for the significant

involvement of serotonin in ADHD. The support for the serotonin hypothesis comes

from the fact that some drugs (TCA & MAOI) that affect serotonin metabolism are moderately effective in ADHD.

However SSRIs have not been shown to be effective.

Thus, if serotonin plays a role in ADHD, it is not likely to have a central role but rather an adjunctive role to one or more other neurotransmitter systems.

Sexual Disorder SSRIs can cause

anorgasmia,  erectile dysfunction, diminished libido.

Stimulation of postsynaptic 5-HT2 and 5-HT3 receptors =decreases dopamine release from the substantia nigra =Sexual Dysfunction.

Impulse Control Disorder Low CSF serotonin metabolites often

found in certain depressions. Also are found among people who have

made suicide attempts who are violent, impulsive, alcoholics and it has been found among their relatives .

Impulsive alcoholic violent offenders have decreased 5-HIAA. 

Eating Disorder and Serotonin Seretonin in ANOREXIA NERVOSA

Three neurotransmitters involved in regulating eating behavior in the paraventricular nucleus of the hypothalamus. Serotonin, Dopamine, Norepinephrine.

Seretonin in BULIMIA NERVOSA Because antidepressants often benefit patients with

bulimia nervosa and because serotonin has been linked to satiety, serotonin and norepinephrine have been implicated.

Seretonin in personality disorders

Studies of personality traits and the dopaminergic and serotonergic systems indicate an arousal-activating function for these neurotransmitters.

Raising serotonin levels with serotonergic agents such as fluoxetine (Prozac) can produce dramatic changes in some character traits of personality.

In many persons, serotonin reduces depression, impulsiveness, and rumination, and can produce a sense of general well-being.

Carcinoid syndrome One type of tumor, called carcinoid,

sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing, diarrhea, and heart problems. Because of serotonin's growth-promoting effect on cardiac myocytes, persons with serotonin-secreting carcinoid may suffer a right heart (tricuspid) valve disease syndrome, caused by proliferation of myocytes onto the valve.

Drugs Affecting Serotonergic System

Serotinergic Drugs 5-HT1A : Buspirone, Ipsapirone, Tandospirone Treat anxiety, depression (partial agonist)

5-HT 1D/1B : Sumatriptan, Naratriptan, Zolmitriptan Treat migraine (partial agonist)

5-HT 2A/2C : Methysergide, Trazodone, Risperidone, Ketanserin, Ritanserin, Mianserin

Treat migraine, depression, schizophrenia (antagonist)

Serotonin effect on Dopamine

Serotonin effect on prolactin

5-HT 3 : Ondansetron, Granisetron, Tropisetron, Memantine, Mirtazapine The enterochromaffin cells are very sensitive

to cancer chemotherapy = vomiting Treat chemotherapy-induced emesis

(antagonist)

5-HT 4 : Cisapride, Metoclopramide, Mosapride, Dazopride, Tegaserod

Treat GI disorders (agonist)

Serotinergic Drugs

Serotinergic drugs Serotonin re–uptake inhibitors

Citalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Venlafaxine

Clomipramine, Imipramine Nefazodone, Trazodone Chlorpheniramine Cocaine, Dextromethorphan, Pentazocine, Pethidine

Serotinergic drugs Irreversible Monoamine oxidase inhibitors

(MAOIs) Clorgyline, Isocarboxazid, Nialamide,

Pargyline, Phenelzine, Tranylcypromine Selegiline Furazolidone Procarbazine

Serotinergic drugs Reversible inhibitors of MAO (RIMAs)

Brofaramine Befloxatone, Toloxatone Moclobemide

Dual Serotonin 2 Antagonists/ Reuptake Inhibitors

These agent acts both presynaptically and postsynaptically.

Eg: nefazodone.

Reference Kaplan and sadock ‘s comprehensive

text book of psychiatry. Stephen M. Stahl – Essential

Psychopharmacology. Medscape.com Emedicine.com

Thank You