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Dr. Rujul Modi
MGMCH, Jaipur
INTRODUCTION
DEFINITION AND CRITERIA FOR NEUROTRANSMITTER
7 PROCESSESS IN NEUROTRANSMITTER ACTION
CLASSIFICATION OF NEUROTRANSMITTERS
BIOGENIC AMINES :
DOPAMINE
SEROTONIN
01
CONTENTS
INTRODUCTION
DISCOVERY OF 1st NEUROTRANSMITTER
 Acetylcholine - The first neurotransmitter identified, in 1926, by
Otto Loewi.
He demonstrated that Acetylcholine
carried, a chemical signal from
vagus nerve to the heart, that
slowed the cardiac rhythm.
Got NOBEL in physiology & medicine in the year 1936
02
 Neurotransmitters are chemical signals released from
presynaptic nerve terminals into the synaptic cleft.
 The subsequent binding of neurotransmitters to specific
receptors on postsynaptic neurons (or other classes of
target cells) transiently changes the electrical properties of
the target cells, leading to an enormous variety of
postsynaptic effects.
03
DEFINITION
1. Molecule is synthesized in neuron
2. Molecule is present in presynaptic neuron & is released on
depolarisation in physiologically significant amount
3. When administered exogenously as a drug, the exogenous
molecule mimics the effect of endogenous neurotransmitter
4. A mechanism in neurons or synaptic cleft acts to remove or
deactivate the neurotransmitter
CRITERIA FOR NEUROTRANSMITTERS
04
05
MAJOR STEPS IN NEUROTRANSMITTER PROCESSING ARE :
1. SYNTHESIS
2. STORAGE
3. RELEASE
4. RECEPTION
5. INACTIVATION
05
1. It is consumed ( broken down or used up) at postsynaptic
membrane leading to action potential generation.
2. Degraded by enzymes present in synaptic cleft.
3. Reuptake mechanism( reutilization). This is the most common
fate.
05
FATE OF NEUROTRANSMITTERS
05
C
L
A
S
S
I
F
I
C
A
T
I
O
N
1. Catecholamines
- Dopamine
- Norepinephrine
- Epinephrine
2. Indolamines
- Serotonin (5-hydroxytryptamine; 5-HT)
3. Histamine
4. Acetylcholine
05
BIOGENIC AMINE NEUROTRANSMITTERS
HISTORY :
 The function of DA as neurotrasmitter was
discovered in 1958 by Arvid carlsson & nils
ake hillarp.
 ARVID CARLSSON got NOBEL for physiology
or medicine in 2000 for showing that DA is
not Just a precursor of NE & E , but a
Neurotransmitter as well.
05
DOPAMINE
14
DOPAMINE SYNTHESIS
5 dopamine pathways in the brain:
1. The MESOLIMBIC DA pathway
2. The MESOCORTICAL DA pathway
3. The NIGROSTRIATAL DA pathway
4. The TUBEROINFUNDIBULAR DA pathway
5. The THALAMIC DA pathway.
DA pathways in the brain can explain the symptoms of schizophrenia as
well as the therapeutic effects and side effects of antipsychotic drugs.
05
DOPAMINE PATHWAYS
05
05
05
Projects from the midbrain Ventral Tegmental Area (VTA) to the
nucleus accumbens, a part of the limbic system
 Plays role in :
- Attention
- Motivation (goal oriented behavior)
- Reward
- Locomotion (pharmacologically induced)
05
1. THE MESOLIMBIC DA PATHWAY
05
Positive Psychotic Symptoms accompanying mania, depression,
dementia.
INCLUDES:
- Delusion
- Hallucination
- Aggression
- Hostility
- Euphoria in drug abusers
05
HYPERACTIVITY OF MESOLIMBIC PATHWAY
- Lack of general motivation & interest,
- Anhedonia
- Negative symptoms,
05
HYPOACTIVITY OF MESOLIMBIC PATHWAY
• Tourette syndrome and ADHD have been linked to a dysfunction
of DA neurotransmission in limbic and cortical region.
Evidenced by the success of dopaminergic drugs in the treatment
of their symptoms.
CTP-Volume-01, 10th edition,
Projects from midbrain Ventral Tegmental Area (VTA) & sends its
axons to areas of the prefrontal cortex
DLPFC VMPFC
Dorsolateral Prefrontal Cortex Ventromedial Prefrontal Cortex
05
2. MESOCORTICAL DA PATHWAY
05
05
Dorsolateral Prefrontal Cortex
(DLPFC) regulates :
Cognition & Executive functions
Hypofunction leads to :
- Cognitive deterioration
- Negative symptoms in
schzophrenia
05
Ventromedial Prefrontal Cortex
(VMPFC) Regulates :
Emotions & Affect
Hypofunction leads to :
- Affective & negative
symptoms
05
- Projects from the substantia nigra to the basal
ganglia or striatum. It is a part of the
extrapyramidal nervous system and plays a key
role in regulating movements. When dopamine
is deficient, it can cause parkinsonism with
tremor, rigidity and akinesia.
-When DA is in excess, it can cause hyperkinetic
movements like tics and dyskinesias.
3. THE NIGROSTRIATAL DA PATHWAY
- Regulates Prolactin secretion.
- Dopamine released from these neurons enters
the circulation and inhibits prolactine secretion
from Anterior pituitary gland.
• Antipsychotic drugs that blocks the dopamine
receptor in Ant. pituitary, induce an increase blood
prolactin level, leads to :
Galactorrhoea , Amenorrhoea, & Sexual dysfunction
05
4. TUBEROINFUNDIBULAR DA PATHWAY
From hypothalamus (Arcuate nucleus) to anterior pituitary.
05
5. THALAMIC DA PATHWAY
• Arises from multiple sites :
- periaqueductal gray
- ventral mesencephalon
- hypothalamic nuclei &
- lateral parabrachial nucleus,
• Projects to the thalamus.
 Function is not currently well known.
 In primates it involves in sleep & arousal mechanisms
They are GPCRs.
5 TYPES : D1, D2, D3, D4, D5
Grouped as,
D1-like and D2-like
(according to their structure,
pharmacolgy & primary
mechanism)
05
DOPAMINE RECEPTORS
05
2 GROUPS
D1-Like D2-Like
( D1 & D5 ) ( D2, D3, D4 )
Activates Gs family
Increase Adenylate cyclase activity
Found postsynaptically on
DA-receptive cell
Activates Gi family
Inhibit Adenylate cyclase activity
Found both postsynaptically &
presynaptically.
DOPAMINE RECEPTORS
• D1 Receptors expressed in the nigrostriatal, mesolimbic and
mesocortical dopamine systems.
• D2 Receptors are more evenly distributed in brain with heighest
levels in striatum and nucleus accumbens.
• Unlike D1-like receptors, D2 receptor may have either a
postsynaptic function or an auto receptor function
06
DOPAMINE RECEPTORS
D2S (short) : Mostly expressed presynaptically & as auto-receptors
D2L (long) : Predominantly a postsynaptic isoform.
• D2 auto receptors may be found on dopaminergic terminals or
on the cell bodies and dendrites of dopaminergic neurons,
where they regulate the neuronal firing rate, synthesis and
release of dopamine through negative feedback.
06
DOPAMINE RECEPTORS
• Furthermore, the over expression of striatal D2 receptors during
brain development can cause long-lasting defects in prefrontal
dopaminergic transmission and working memory in mice, a
finding relevant to neurodevelopmental hypotheses of
schizophrenia.
06
DOPAMINE RECEPTORS
• D3 receptors can operate as auto-receptors to complement the
D2 auto-receptor role, in regulation of dopamine release.
• D2 receptors are also expressed in the anterior pituitary and
mediate the
- Dopaminergic inhibition of prolactin and
- Melanocyte stimulating hormone release.
06
DOPAMINE RECEPTORS
• Catalepsy induced by neuroleptics such as haloperidol appears
to be largely mediated by the D2L receptor
• Post mortem analyses of schizophrenic brains reveals
elevations in D2 receptor density.
06
DOPAMINE RECEPTORS
• Some Older Typical antipsychotic drugs like “Chlorpromazine”
blocks both D1 & D2 receptors. While Haloperidol are selective for
D2 receptors.
• All Atypical antipsychotic drugs effectively block D2 receptors
with little/no impact on D1. Aripiprazole is a partial D2 agonist.
• Among Atypical antipsychotics Resperidone has high affinity for
D2 receptors.
06
DOPAMINE RECEPTORS
• So resperidone is more prone to induce hyperprolactinemia, than
other atypical antipsychotics.
• The Clozapine has an important role in combatting treatment-
resistant schizophrenia. The success of clozapine was initially
linked to it’s antagonism of D4 receptors which distinguishes it
from other antipsychotics.
• Olanzapine has the closest receptor profile to clozapine.
06
DOPAMINE RECEPTORS
11
• D3 receptor expression is highest in the nucleus accumbens.
• The highest levels of D4 receptors are expressed in
- frontal cortex, midbrain, amygdala, hippocampus, and medulla
• D4 receptors are abundant in the heart and kidney.
11
SEROTONIN
• 2% in CNS
• 98% in PERIPHERY
- 80% in G.I. Tract (motility & contractility)
- 15-18% in Mast cells & platelets (aggreg. & clotting)
• 5HT Cannot cross B.B.B.
11
SEROTONIN
Clustered in midline raphe nuclei of brainstem
1. ROSTRAL NUCLEI- sends ascending axonal projections
throughout the brain
2. CAUDAL NUCLEI – sends projections to medulla, cerebellum &
spinal cord
• Innervation of dorsal horns – implicated in suppression of
noceceptive pathways, relate to pain relieving effect of some
antidepressants
SEROTONIN SYNTHESIS
TRYPTOPHAN
TPH
5- HYDROXYTRYPTOPHAN
AADC
SEROTONIN (5-HYDROXYTRPTAMINE)
HOMT
MELATONIN
TPH= Tryptophan hydroxylase
AADC = Aromatic amino acid decarboxylase
HOMT = Hydroxyindol O methyletransferase
11
SEROTONIN
• Rostral System: The Rostral midbrain cluster of cells (raphe
nuclei) are distributed throughout the midbrain, it provides over
80% of the 5-HT innervation of the forebrain.
• Sends projections to –Prefrontal cortex, basal forebrain,
striatum, nucleus accumbens, thalamus, hypothalamus,
amygdala, & hippocampus
11
SEROTONIN
• MEDIAN RAPHE NUCLEUS: sends projections predominantly to
Limbic system including hippocampus.
• DORSAL RAPHE NUCLEUS: sends predominantly to striatum &
thalamus.
• Projections from these nuclei, course through the MEDIAN
FOREBRAIN BUNDLE before diverging to many regions.
11
7 types of serotonin receptors are now recognized:
5-HT1 to 5-HT7, with numerous subtypes, totaling 14 distinct
receptors. All serotonin receptors are GPCRs except 5HT3
• The 5-HT1- is the largest serotonin receptor subfamily,
• 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, & 5-HT1F
SEROTONIN RECEPTORS
11
5HT1A :
• Postsynaptic membranes of forebrain neurons primarily in the -
hippocampus, cortex, septum and on serotonergic neurons,
Where it functions as an inhibitory somatodendritic auto
receptor
SEROTONIN RECEPTORS : 5HT1
11
• The down regulation of 5-HT1A auto receptors by the chronic
administration of serotonin reuptake inhibitors has been
implicated in their antidepressant effects
• Partial 5-HT1A receptor agonists such as buspirone display both
anxiolytic and antidepressant properties.
SEROTONIN RECEPTORS
5HT1B & 5HT1D :
 Resemble each other in structure and brain localization, although the
5-HT1D receptor is expressed at lower levels.
 5HT1B - implicated in the modulation of locomotor activity levels,
consistent with its high level of expression in basal ganglia also been
suggested as a modulator of aggression.
• Although 5-HT1B receptor agonist drugs have shown limited clinical
efficacy as anti aggressive agents.
14
SEROTONIN RECEPTORS
• In addition, 5-HT1B and the 5-HT1D receptors are found in the
cerebral vasculature and the trigeminal ganglion, respectively,
and are stimulated by the anti migraine drug Sumatriptan.
• These receptors may therefore be involved in the therapeutic
efficacy of this drug, possibly mediating vasoconstriction and
inhibition of noceceptive transmission
14
SEROTONIN RECEPTORS
5-HT1E Receptors :
- Enriched in Hippocampus, making it s possible drig target for
memory disorders such as Alzheirmer disease/ TLE
5-HT1F Receptors :
- Dorsal raphe nucleus,
- Hippocampus,
- Cortex, and Striatum
14
SEROTONIN RECEPTORS
5HT2A Receptors : neocortex , platelets and smooth muscle
• Much recent attention has focused on the contributions of
5-HT2A/C receptors to the actions of atypical antipsychotic drugs
such as clozapine, risperidone and olanzapine.
• There is some evidence that downregulation 5HT2A/C receptors
enhance antidepressant effect of SSRIs.
14
SEROTONIN RECEPTORS : 5HT2
• In agreement with this hypothesis is evidence of the
effectiveness of antipsychotic drugs given with SSRIs, in
treatment resistant depression.
• 5-HT2A receptor has also been implicated in the cognitive
process of working memory, a function believed to be impaired in
schizophrenia.
14
SEROTONIN RECEPTORS : 5HT2
5HT2B Receptors :
 contributes to the contractile effects of serotonin in the stomach
fundus and plays important roles in cardiac development.
5HT2C Receptors :
- hippocampal formation, prefrontal cortex, amygdala, striatum,
hypothalamus & choroid plexus
14
SEROTONIN RECEPTORS : 5HT2
• Stimulation of 5-HT2C receptors has been proposed to produce
anxiogenic effects as well as anorectic effects, which may result
from interactions with the hypothalamic melanocortin and leptin
pathways.
• 5-HT2C also play a role in the weight gain and development of
type II diabetes mellitus associated with atypical antipsychotic
treatment.
14
SEROTONIN RECEPTORS
• Alterations in 5-HT2C receptor mRNA editing have been found in
the brains of suicide victims with a history of major depression,
and SSRIs have been shown to alter these editing patterns.
5HT3 :
• Hippocampus, neocortex, amygdala, hypothalamus, brainstem,
including the area postrema.
• Peripherally - pituitary gland and enteric nervous system
14
SEROTONIN RECEPTORS
• 5-HT3 receptor antagonists such as ondansetron are used as
antiemetic agents and are under evaluation as potential
antianxiety and cognitive-enhancing agents.
• 5HT4 : Partial agonists used in IBS (TEGASEROD)
• 5HT5, 5-HT6, 5HT7 receptors : Unclear action
Antagonists may have antidepressant action
14
SEROTONIN RECEPTORS
• Serotonin is a key regulatory of appetite, sleep, and aggression.
ROLE IN PSYCHIATRY
Affective Disorders : Low levels of 5-HT and metabolites are
associated with severe depression
Recent studies indicate that this type of 5-HT influence may start
early in life; low levels of 5HIAA have been found in children and
adolescents with disruptive behavioral disorders.
14
SEROTONIN RECEPTORS
• Obsessive Compulsive Disorder : 5-HT dysfunction has been
associated with obsessive compulsive disorder. Accordingly,
selective 5-HT uptake blockers are used as a therapy for this
condition.
• Migraine Headaches :5-HT1 agonists are used for the treatment of
migraine headache.
• Insomnia : The role of 5-HT in sleep regulation has lead to the
hypothesis that reduced levels of 5-HT may induce insomnia.
14
SEROTONIN RECEPTORS
THANK YOU
18

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Neurotransmitters- serotonin & dopamine by dr. rujul modi

  • 2. INTRODUCTION DEFINITION AND CRITERIA FOR NEUROTRANSMITTER 7 PROCESSESS IN NEUROTRANSMITTER ACTION CLASSIFICATION OF NEUROTRANSMITTERS BIOGENIC AMINES : DOPAMINE SEROTONIN 01 CONTENTS
  • 3. INTRODUCTION DISCOVERY OF 1st NEUROTRANSMITTER  Acetylcholine - The first neurotransmitter identified, in 1926, by Otto Loewi. He demonstrated that Acetylcholine carried, a chemical signal from vagus nerve to the heart, that slowed the cardiac rhythm. Got NOBEL in physiology & medicine in the year 1936 02
  • 4.  Neurotransmitters are chemical signals released from presynaptic nerve terminals into the synaptic cleft.  The subsequent binding of neurotransmitters to specific receptors on postsynaptic neurons (or other classes of target cells) transiently changes the electrical properties of the target cells, leading to an enormous variety of postsynaptic effects. 03 DEFINITION
  • 5. 1. Molecule is synthesized in neuron 2. Molecule is present in presynaptic neuron & is released on depolarisation in physiologically significant amount 3. When administered exogenously as a drug, the exogenous molecule mimics the effect of endogenous neurotransmitter 4. A mechanism in neurons or synaptic cleft acts to remove or deactivate the neurotransmitter CRITERIA FOR NEUROTRANSMITTERS 04
  • 6. 05 MAJOR STEPS IN NEUROTRANSMITTER PROCESSING ARE : 1. SYNTHESIS 2. STORAGE 3. RELEASE 4. RECEPTION 5. INACTIVATION
  • 7. 05
  • 8. 1. It is consumed ( broken down or used up) at postsynaptic membrane leading to action potential generation. 2. Degraded by enzymes present in synaptic cleft. 3. Reuptake mechanism( reutilization). This is the most common fate. 05 FATE OF NEUROTRANSMITTERS
  • 10. 1. Catecholamines - Dopamine - Norepinephrine - Epinephrine 2. Indolamines - Serotonin (5-hydroxytryptamine; 5-HT) 3. Histamine 4. Acetylcholine 05 BIOGENIC AMINE NEUROTRANSMITTERS
  • 11. HISTORY :  The function of DA as neurotrasmitter was discovered in 1958 by Arvid carlsson & nils ake hillarp.  ARVID CARLSSON got NOBEL for physiology or medicine in 2000 for showing that DA is not Just a precursor of NE & E , but a Neurotransmitter as well. 05 DOPAMINE
  • 13. 5 dopamine pathways in the brain: 1. The MESOLIMBIC DA pathway 2. The MESOCORTICAL DA pathway 3. The NIGROSTRIATAL DA pathway 4. The TUBEROINFUNDIBULAR DA pathway 5. The THALAMIC DA pathway. DA pathways in the brain can explain the symptoms of schizophrenia as well as the therapeutic effects and side effects of antipsychotic drugs. 05 DOPAMINE PATHWAYS
  • 14. 05
  • 15. 05
  • 16. 05
  • 17. Projects from the midbrain Ventral Tegmental Area (VTA) to the nucleus accumbens, a part of the limbic system  Plays role in : - Attention - Motivation (goal oriented behavior) - Reward - Locomotion (pharmacologically induced) 05 1. THE MESOLIMBIC DA PATHWAY
  • 18. 05
  • 19. Positive Psychotic Symptoms accompanying mania, depression, dementia. INCLUDES: - Delusion - Hallucination - Aggression - Hostility - Euphoria in drug abusers 05 HYPERACTIVITY OF MESOLIMBIC PATHWAY
  • 20. - Lack of general motivation & interest, - Anhedonia - Negative symptoms, 05 HYPOACTIVITY OF MESOLIMBIC PATHWAY • Tourette syndrome and ADHD have been linked to a dysfunction of DA neurotransmission in limbic and cortical region. Evidenced by the success of dopaminergic drugs in the treatment of their symptoms. CTP-Volume-01, 10th edition,
  • 21. Projects from midbrain Ventral Tegmental Area (VTA) & sends its axons to areas of the prefrontal cortex DLPFC VMPFC Dorsolateral Prefrontal Cortex Ventromedial Prefrontal Cortex 05 2. MESOCORTICAL DA PATHWAY
  • 22. 05
  • 23. 05
  • 24. Dorsolateral Prefrontal Cortex (DLPFC) regulates : Cognition & Executive functions Hypofunction leads to : - Cognitive deterioration - Negative symptoms in schzophrenia 05 Ventromedial Prefrontal Cortex (VMPFC) Regulates : Emotions & Affect Hypofunction leads to : - Affective & negative symptoms
  • 25. 05 - Projects from the substantia nigra to the basal ganglia or striatum. It is a part of the extrapyramidal nervous system and plays a key role in regulating movements. When dopamine is deficient, it can cause parkinsonism with tremor, rigidity and akinesia. -When DA is in excess, it can cause hyperkinetic movements like tics and dyskinesias. 3. THE NIGROSTRIATAL DA PATHWAY
  • 26. - Regulates Prolactin secretion. - Dopamine released from these neurons enters the circulation and inhibits prolactine secretion from Anterior pituitary gland. • Antipsychotic drugs that blocks the dopamine receptor in Ant. pituitary, induce an increase blood prolactin level, leads to : Galactorrhoea , Amenorrhoea, & Sexual dysfunction 05 4. TUBEROINFUNDIBULAR DA PATHWAY From hypothalamus (Arcuate nucleus) to anterior pituitary.
  • 27. 05 5. THALAMIC DA PATHWAY • Arises from multiple sites : - periaqueductal gray - ventral mesencephalon - hypothalamic nuclei & - lateral parabrachial nucleus, • Projects to the thalamus.  Function is not currently well known.  In primates it involves in sleep & arousal mechanisms
  • 28. They are GPCRs. 5 TYPES : D1, D2, D3, D4, D5 Grouped as, D1-like and D2-like (according to their structure, pharmacolgy & primary mechanism) 05 DOPAMINE RECEPTORS
  • 29. 05 2 GROUPS D1-Like D2-Like ( D1 & D5 ) ( D2, D3, D4 ) Activates Gs family Increase Adenylate cyclase activity Found postsynaptically on DA-receptive cell Activates Gi family Inhibit Adenylate cyclase activity Found both postsynaptically & presynaptically. DOPAMINE RECEPTORS
  • 30. • D1 Receptors expressed in the nigrostriatal, mesolimbic and mesocortical dopamine systems. • D2 Receptors are more evenly distributed in brain with heighest levels in striatum and nucleus accumbens. • Unlike D1-like receptors, D2 receptor may have either a postsynaptic function or an auto receptor function 06 DOPAMINE RECEPTORS
  • 31. D2S (short) : Mostly expressed presynaptically & as auto-receptors D2L (long) : Predominantly a postsynaptic isoform. • D2 auto receptors may be found on dopaminergic terminals or on the cell bodies and dendrites of dopaminergic neurons, where they regulate the neuronal firing rate, synthesis and release of dopamine through negative feedback. 06 DOPAMINE RECEPTORS
  • 32. • Furthermore, the over expression of striatal D2 receptors during brain development can cause long-lasting defects in prefrontal dopaminergic transmission and working memory in mice, a finding relevant to neurodevelopmental hypotheses of schizophrenia. 06 DOPAMINE RECEPTORS
  • 33. • D3 receptors can operate as auto-receptors to complement the D2 auto-receptor role, in regulation of dopamine release. • D2 receptors are also expressed in the anterior pituitary and mediate the - Dopaminergic inhibition of prolactin and - Melanocyte stimulating hormone release. 06 DOPAMINE RECEPTORS
  • 34. • Catalepsy induced by neuroleptics such as haloperidol appears to be largely mediated by the D2L receptor • Post mortem analyses of schizophrenic brains reveals elevations in D2 receptor density. 06 DOPAMINE RECEPTORS
  • 35. • Some Older Typical antipsychotic drugs like “Chlorpromazine” blocks both D1 & D2 receptors. While Haloperidol are selective for D2 receptors. • All Atypical antipsychotic drugs effectively block D2 receptors with little/no impact on D1. Aripiprazole is a partial D2 agonist. • Among Atypical antipsychotics Resperidone has high affinity for D2 receptors. 06 DOPAMINE RECEPTORS
  • 36. • So resperidone is more prone to induce hyperprolactinemia, than other atypical antipsychotics. • The Clozapine has an important role in combatting treatment- resistant schizophrenia. The success of clozapine was initially linked to it’s antagonism of D4 receptors which distinguishes it from other antipsychotics. • Olanzapine has the closest receptor profile to clozapine. 06 DOPAMINE RECEPTORS
  • 37. 11 • D3 receptor expression is highest in the nucleus accumbens. • The highest levels of D4 receptors are expressed in - frontal cortex, midbrain, amygdala, hippocampus, and medulla • D4 receptors are abundant in the heart and kidney.
  • 38. 11 SEROTONIN • 2% in CNS • 98% in PERIPHERY - 80% in G.I. Tract (motility & contractility) - 15-18% in Mast cells & platelets (aggreg. & clotting) • 5HT Cannot cross B.B.B.
  • 39. 11 SEROTONIN Clustered in midline raphe nuclei of brainstem 1. ROSTRAL NUCLEI- sends ascending axonal projections throughout the brain 2. CAUDAL NUCLEI – sends projections to medulla, cerebellum & spinal cord • Innervation of dorsal horns – implicated in suppression of noceceptive pathways, relate to pain relieving effect of some antidepressants
  • 40. SEROTONIN SYNTHESIS TRYPTOPHAN TPH 5- HYDROXYTRYPTOPHAN AADC SEROTONIN (5-HYDROXYTRPTAMINE) HOMT MELATONIN TPH= Tryptophan hydroxylase AADC = Aromatic amino acid decarboxylase HOMT = Hydroxyindol O methyletransferase
  • 41. 11 SEROTONIN • Rostral System: The Rostral midbrain cluster of cells (raphe nuclei) are distributed throughout the midbrain, it provides over 80% of the 5-HT innervation of the forebrain. • Sends projections to –Prefrontal cortex, basal forebrain, striatum, nucleus accumbens, thalamus, hypothalamus, amygdala, & hippocampus
  • 42. 11 SEROTONIN • MEDIAN RAPHE NUCLEUS: sends projections predominantly to Limbic system including hippocampus. • DORSAL RAPHE NUCLEUS: sends predominantly to striatum & thalamus. • Projections from these nuclei, course through the MEDIAN FOREBRAIN BUNDLE before diverging to many regions.
  • 43. 11 7 types of serotonin receptors are now recognized: 5-HT1 to 5-HT7, with numerous subtypes, totaling 14 distinct receptors. All serotonin receptors are GPCRs except 5HT3 • The 5-HT1- is the largest serotonin receptor subfamily, • 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, & 5-HT1F SEROTONIN RECEPTORS
  • 44. 11 5HT1A : • Postsynaptic membranes of forebrain neurons primarily in the - hippocampus, cortex, septum and on serotonergic neurons, Where it functions as an inhibitory somatodendritic auto receptor SEROTONIN RECEPTORS : 5HT1
  • 45. 11 • The down regulation of 5-HT1A auto receptors by the chronic administration of serotonin reuptake inhibitors has been implicated in their antidepressant effects • Partial 5-HT1A receptor agonists such as buspirone display both anxiolytic and antidepressant properties. SEROTONIN RECEPTORS
  • 46. 5HT1B & 5HT1D :  Resemble each other in structure and brain localization, although the 5-HT1D receptor is expressed at lower levels.  5HT1B - implicated in the modulation of locomotor activity levels, consistent with its high level of expression in basal ganglia also been suggested as a modulator of aggression. • Although 5-HT1B receptor agonist drugs have shown limited clinical efficacy as anti aggressive agents. 14 SEROTONIN RECEPTORS
  • 47. • In addition, 5-HT1B and the 5-HT1D receptors are found in the cerebral vasculature and the trigeminal ganglion, respectively, and are stimulated by the anti migraine drug Sumatriptan. • These receptors may therefore be involved in the therapeutic efficacy of this drug, possibly mediating vasoconstriction and inhibition of noceceptive transmission 14 SEROTONIN RECEPTORS
  • 48. 5-HT1E Receptors : - Enriched in Hippocampus, making it s possible drig target for memory disorders such as Alzheirmer disease/ TLE 5-HT1F Receptors : - Dorsal raphe nucleus, - Hippocampus, - Cortex, and Striatum 14 SEROTONIN RECEPTORS
  • 49. 5HT2A Receptors : neocortex , platelets and smooth muscle • Much recent attention has focused on the contributions of 5-HT2A/C receptors to the actions of atypical antipsychotic drugs such as clozapine, risperidone and olanzapine. • There is some evidence that downregulation 5HT2A/C receptors enhance antidepressant effect of SSRIs. 14 SEROTONIN RECEPTORS : 5HT2
  • 50. • In agreement with this hypothesis is evidence of the effectiveness of antipsychotic drugs given with SSRIs, in treatment resistant depression. • 5-HT2A receptor has also been implicated in the cognitive process of working memory, a function believed to be impaired in schizophrenia. 14 SEROTONIN RECEPTORS : 5HT2
  • 51. 5HT2B Receptors :  contributes to the contractile effects of serotonin in the stomach fundus and plays important roles in cardiac development. 5HT2C Receptors : - hippocampal formation, prefrontal cortex, amygdala, striatum, hypothalamus & choroid plexus 14 SEROTONIN RECEPTORS : 5HT2
  • 52. • Stimulation of 5-HT2C receptors has been proposed to produce anxiogenic effects as well as anorectic effects, which may result from interactions with the hypothalamic melanocortin and leptin pathways. • 5-HT2C also play a role in the weight gain and development of type II diabetes mellitus associated with atypical antipsychotic treatment. 14 SEROTONIN RECEPTORS
  • 53. • Alterations in 5-HT2C receptor mRNA editing have been found in the brains of suicide victims with a history of major depression, and SSRIs have been shown to alter these editing patterns. 5HT3 : • Hippocampus, neocortex, amygdala, hypothalamus, brainstem, including the area postrema. • Peripherally - pituitary gland and enteric nervous system 14 SEROTONIN RECEPTORS
  • 54. • 5-HT3 receptor antagonists such as ondansetron are used as antiemetic agents and are under evaluation as potential antianxiety and cognitive-enhancing agents. • 5HT4 : Partial agonists used in IBS (TEGASEROD) • 5HT5, 5-HT6, 5HT7 receptors : Unclear action Antagonists may have antidepressant action 14 SEROTONIN RECEPTORS
  • 55. • Serotonin is a key regulatory of appetite, sleep, and aggression. ROLE IN PSYCHIATRY Affective Disorders : Low levels of 5-HT and metabolites are associated with severe depression Recent studies indicate that this type of 5-HT influence may start early in life; low levels of 5HIAA have been found in children and adolescents with disruptive behavioral disorders. 14 SEROTONIN RECEPTORS
  • 56. • Obsessive Compulsive Disorder : 5-HT dysfunction has been associated with obsessive compulsive disorder. Accordingly, selective 5-HT uptake blockers are used as a therapy for this condition. • Migraine Headaches :5-HT1 agonists are used for the treatment of migraine headache. • Insomnia : The role of 5-HT in sleep regulation has lead to the hypothesis that reduced levels of 5-HT may induce insomnia. 14 SEROTONIN RECEPTORS