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.
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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
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
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
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
19. Positive Psychotic Symptoms accompanying mania, depression,
dementia.
INCLUDES:
- Delusion
- Hallucination
- Aggression
- Hostility
- Euphoria in drug abusers
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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
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)
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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.
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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.
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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.
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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
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.
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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
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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
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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.
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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.
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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
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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.
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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
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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
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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.
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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.
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SEROTONIN RECEPTORS
