2. • Neurotransmitter :- Defined as a chemical
messenger that carries, boosts, and balances
signals between neurons , or nerve cells, and
other cells in the body.
• They are released from presynaptic nerve
terminals into the synaptic cleft.
• Enable neurotransmission
DEFINITION
3. • Criteria:-
• It is synthesised by a neuron.
• It is present in the presynaptic terminal and is released in
amounts sufficient to exert a defined action on a
postsynaptic neuron or effector organ
• Substance must be released in response to presynaptic
depolarisation which must occur in calcium dependent
manner.
• Specific receptor for the substance must be present on
postsynaptic cell.
4.
5. Synthesised from precursors under the influence of enzymes
Stored in vesicles
Action potential arrives at axon terminal
Voltage gated calcium channels open and calcium enters the cell
Fusion of synaptic vesicles with presynaptic membrane
Exocytosis occurs
Release of neurotransmitter
11. Dopamine receptors
Receptor
subtype
D1 D2 D3 D4 D5
Gprotein Gs Gi Gi Gi Gs
Localisation Caudate,
Putamen,
Nucleus
accumbens
Caudate,
putamen,
NA
Nucleus
accumbens
Frontal cortex,
Midbrain,
Amygdala
Hippocampus
Hypothalamus
Action Locomotion
Reward
reinforcement
Learning
Memory
Locomotion
Reward
reinforcement
Learning
Locomotion,
Role in
cognition
And emotion
- Learning and
memory
12. • Once synthesized, dopamine is released into synaptic clefts.
• Further on; 2 routes-
✓ Reuptake into synaptic vesicle and reuse as a
neurotransmitter
✓ Metabolism by MAO and COMT enzymes ; with
eventual formation of Homovanillic acid.
13. 1. MESOLIMBIC- VTA to ventral straitum
2. MESOCORTICAL- Ventral tegmental area to cerebral
cortex
3. NIGRIOSTRIATAL – Substantia nigra to dorsal straitum
4. TUBEROHYPOPHYSEAL- Hypothalamic Arcuate
And Paraventricular Nuclei To Pituatary Gland
5. MESOACCUMBENS PATHWAY
DOPAMINERGIC PATHWAYS
16. • MESOACCUMBENS PATHWAY
-Central element in the neural representation of reward.
- Plastic changes in this pathway are thought to underlie
drug addiction.
17. • Dopamine reuptake transport pumps are few in prefrontal cortex
unlike other brain areas. So dopamine acts in prefrontal cortex via
volume neurotransmission.
• Volume neurotransmission is neurotransmission without synapse .
AKA Non synaptic Diffusion neurotransmission.
• Dopamine is free to spill over from that synapse and diffuse to
neighbouring dopamine receptor to stimulate them.
18. • 5- HYDROXY TRYPTAMINE
• Highest concentration in platelets and GIT
(enterochromaffin cells and myenteric plexus)
• FROM - Caudal and rostral raphe nuclei
• TO - Amygdala , Cingulate gyrus , Straitum ,
Hippocampus , Thalamus
2. SEROTONIN
23. • 5 HT1A antagonism - improvement of positive symptoms.
1. Decrease glutamate release
2. Decreases dopamine release.
• Release of dopamine via inactivation of 5HT2A receptors in the
meso-cortical area prevents occurrence of negative symptoms..
SCHIZOPHRENIA
26. • Increased 5HT2A receptors in caudate
nucleus
• Increased activations in the cortico-striato-
thalamo-cortical circuit, particularly in the
caudate, putamen, anterior thalamus,
orbitofrontal cortex, amygdala, and brain
stem.
OCD
27. • Originate from the tubero-mamillary nucleus of the
posterior hypothalamus and send projections to most
parts of the brain.
• Arousal, control of pituitary hormone secretion,
suppression of eating and cognitive functions.
• G-protein-coupled H1-H4 receptors.
• Wake-promoting substance - treat sleep-wake disorders,
especially narcolepsy, via modulation of H3 receptor
function.
• Involved in the pain perception.
3. HISTAMINE
29. SUBTYPE ACTION
H1 Antagonism produces sedation and
weight gain
H2 Antagonism is useful in management of
peptic ulcer
H3 Antagonism leads to arousal and
appetite suppression
RECEPTORS
30. The central histamine system is involved in many brain functions
such as arousal, control of pituitary hormone secretion, suppression
of eating and cognitive functions.
its role in wake-promoting substance to treat sleep-wake disorders,
especially narcolepsy.
Brain histamine levels are decreased in Alzheimer's disease. High
histamine concentrations are found in the brains of Parkinson's
disease and schizophrenic patients.
Low histamine levels are associated with convulsions and seizures.
Clinical Implication
31. • Acetylcholine was the first neurotransmitter discovered and it
was originally described as vagus puff because of its ability to
mimic the electrical stimulation of the vagus nerve.
• it is now known to be a neurotransmitter at all autonomic ganglia,
at the neuromuscular junction and at many synapses in the CNS.
ACETYLCHOLINE
32. Acetyl coA + choline
Acetylcholine
SYNTHESIS
Choline acetyltransferase
33. • In CNS Ach is found primarily in interneurons.
• Many cholinergic pathways have been identified.
• The most important is the cholinergic projection from the
NUCLEUS OF BASALIS MEYNERT (in the basal forebrain) to the
forebrain neocortex and associated limbic structures.
34. • Degeneration of this pathway is one of the pathologies associated
with ALZHEIMER’S DISEASE.
• Degeneration of this pathway is one of the pathologies associated
with ALZHEIMER’S DISEASE
• Therefore , drugs that promote acetylcholine signaling are
beneficial.
35. • The Mesopontine Complex – consists of cholingeric neurons
within pedunculopontine and tegmetal nuclie which provide
innervation to thalamus and brainstem regions such as LC.
• Modulation of Cholinergic INTERNEURONS of STRIATUM has
been implicated in the antiparkinsonian actions of anticholinergic
agents.
36. • From - Locus coerulus , lateral tegmental
noradrenergic nuclei
• To – neocortex , Thalamus , Hippocampus and
midbrain tectum
5. EPINEPHRINE AND NOR-
EPINEPHRINE
38. SUBTYPES ACTIONS
α1A,B,D Antagonists act as antihypertensives
α2A,B,C Antagonists act as sedatives and
antihypertensives
β1 Linked to cardiac function
β2 Regulation of bronchial muscle
contraction
β3 Regulation of adipose tissue function
RECEPTORS
39. • Monoamine hypothesis of Depression postulates deficiency of
serotonin and norepinephrine neurotransmission in the brain.
• Currently available antidepressants act on one or more
mechanism compatible with the monoamine hypothesis which
include inhibition of re-uptake of serotonin or norepinephrine and
antagonism of presynaptic inhibitory norepinephrine or serotonin
receptors.
Clinical Implication
40. • Reduced NE neurotransmission is associated with decreased
alertness, low energy, problems of inattention, concentration and
cognitive ability.
• NE plays a determinant role in executive functioning regulating
cognition, motivation , and intellect, which are fundamental in
social relationships.
• Social dysfunction is possibly one of the most important factors
affecting the quality of life in depressed patients.
41. 1.Amino acid neurotransmitter at excitatory synapses are
A) Aspartate
B) Glutamate
Amino Acid Neurotransmitters at inhibitory synapses are
A) Glycine
B) GABA
Amino acid Neurotransmitter
42. • Non Essential Amino Acid
• Acts as a neurotransmitter in CNS
• Called king of Neurotransmitter
• Major Excitatory neurotransmitter
• Present in 80% of brain synapses esp dendritic spines.
Glutamic Acid/Glutamate
43. • It is exluded from BBB and is synthesised denovo from
Glucose via krebs cycle
Glutamate recycling called Glutamine cycle
Aspartate
Alpha oxo glutarate
• Of these 40% of glutamate for neurotransmission is obtained by
glutamine cycle.
• 20% from glucose through Kreb’s cycle.
BioSynthesis
44. • Glutamte is transported across membranes of synapses by Na
dependent transporter called EAATs
• 5 types
EAAT1-Astrocyte
EAAT2-astrocyte,forebrain-implicated in ALS
EAAT3-UMN
EAAT4-cerebellar purkinje cells.
EAAT5-Retina
• Of these EAAT1 & 2 are involved in the reuptake and release of
glutamate during glutamine cycle.
Transporters
45. • VGLUTs are expressed in presynaptic neuron for transport of
glutamate into vesicles once it is synthesized.
• There are 3 types:-
VGLUT1-cortex
VGLUT2-Diencephalon,Brainstem.
VGLUT3-cotransmission in non glutamatergic neurons.
Vesicular Glutamate transporter
47. • Excessive glutamate is linked to stress, degenerative diseases
like Alzheimer’s and Huntington’s .
• Abnormalities of glutamatergic neurotransmission or glutamatergic
dysfunction lead to the development of major psychiatric disorders
namely - Schizophrenia ,Bipolar disorder and major depressive
disorder.
CLINICAL IMPLICATIONS
48. • Glutamatergic neurotransmission could be critical for the
pathophysiology of schizophrenia For eg administration of NMDA
receptor antagonist like phencyclidine or ketamine induce
schizophrenia like state .
• There is reduced expression of NMDR in prefrontal cortex in
bipolar disorder.
• Expression of mGLUR2/3 receptor in the anterior cingulate cortex
is reduced in a patient with MDD.
49. • Drugs of abuse increase expression of GluR1 in VTA(ventral
tegmental are) of midbrain leading to sensitization.
• Lithium and valproate are known to decrease GluR1 in these
regions.
• Anti depressants, mood stabilizers like lamotrigine and riluzole
increase GluR1 and GluR2 in hippocampal area.
51. • Major inhibitory amino acid neurotransmitter
• Has broad distribution in CNS
• Synthesized from glutamate by glutamic acid decarboxylase(GAD)
which catalyzes and removes alpha carboxyl group. GAD is
restricted to GABAergic nerve terminals in CNS and islet cells in
periphery.
52. • 2 major classes:-
• GABA A Receptors
• GABA B Receptors
• Minor class
• GABA C receptors
GABA RECEPTORS
54. • Ischemic stroke
• Alzheimer’s disease
• Degenerative dementia
• Parkinson’s
• ALS
• Epilepsy- Compounds that antagonize the action of glutamte at
NMDA receptors or AMPA/KA receptors are generally effective in
blocking seizures
Clinical Implications
55. • Ethanol-enhances GABA function in VTA and attenuates
NMDA receptor function VTA
• Chronic abuse causes down regulation of GABA A and up
regulation of NMDA
• Hence during acute discontinuation there is hyper excitable
state due to excess glutamate release characterised by
delirium tremens.
• Acamprosate blocks mGlu5 and mGlu2,also acts indirectly as
NMDA anatgonists and agonists to GABA system.
• Microencephaly associated with fetal alcohol exposure results
from inhibition of NMDA receptor funtion , resulting in
widespread neuronal apoptosis in the immature cortex.
56. • Inhibitory neurotransmitter primarily in brain stem and spinal cord
• Synthesis:-Non essential AA synthesized in Brain
L-serine forms Glycine in the presence of serine hydroxylase &
ethyl transferase.
• Psychiatric aspect:
Schizophrenia-decreased glycine levels.
Glycine
57. • They does not fulfill the criteria of classical neurotransmitters
◦ Endocannabinoids
◦ Nitric oxide
◦ Carbon monoxide
◦ Hydrogen sulfide
◦ D-serine
Novel neurotransmitters
58. • Endocannabinoids, the endogenous ligands, are polyunsaturated
fatty acid derivatives that bind to cannabinoid receptors
• Two types of receptors CB1 and CB2
• Both metabotropic receptors - both are 7 transmembrane domain
macromolecules of the G protein coupled class.
• CB1 found at highest concentrations in the hippocampus,
neocortex, basal ganglia, and cerebellum
• Also found in the basolateral amygdala, hypothalamus, and
midbrain
Endocannabinoids
59. • Endocannabinoids
are synthesized in the
postsynaptic neuron
and then released
and diffuse to
presynaptic
cannabinoid receptors
such as the CB1 or
cannabinoid 1
receptor
60. • There is close involvement of CB1 receptor in stress regulation and
the development of mood disorders , in post traumatic stress disorder
as well as in schizophrenia and ADHD, eating disorders. Elevated
levels of Anandamide, an endogenous cannabinoid agonist, have
been found in the CSF fluid of persons with schizophrenia . A case-
control study found that persons with schizophrenia had a greater
density of CB1 receptors in the prefrontal cortex than controls .
• The endocannabinoids also play a prominent role in stress and
anxiety.
61. • Nitric oxide is synthesised
postsynaptically and then
diffuses out of the
postsynaptic membrane
and into the presynaptic
me,brand and into the
presynaptic membrane to
interact with cyclic
guanosine mono
phosphate (cGMP)
sensitive targets there.
Nitric oxide
62. • The effects of NO are mediated primarily by cGMP & glutamate.
• NO- cGMP system is required for activity dependent synaptic
plasticity in various brain areas such as hippocampus ,amygdala ,
striatum, cerebral cortex and cerebellum.
• No has been linked to the release of other neurotransmitters & the
effects which they produce ,in particular Ach
,noradrenaline,dopamine ,glutamate and GABA .
63. • The wide spectrum of NO associated psychiatric disorders include
Alzheimer’s disease as well as schizophrenia, mood & eating
disorders.
• No possesses properties of both pro and antioxidants .so it is able
to stimulate peroxidation of lipids & mediate antioxidants reactions
in cellular membranes.
• However free NO can bind with superoxide forming highly toxic
peroxynitrite .
Clinical Implication
64. • There is association of oxidative stress with psychosis and
schizophrenia.
• Investigations have revealed that significant disturbances in NO
levels in the brain structures like cerebellum ,hypothalamus
,hippocampus ,striatum & fluids of subjects with schizophrenia.
65. • Carbon monoxide (CO) is formed physiologically by
heme oxygenase (HO). HO cleaves the porphyrin ring of
heme to form biliverdin, which is rapidly reduced by
biliverdin reductase to bilirubin.
• CO diffuses through membranes to target cells, where it
can bind the heme of soluble guanylate cyclase (sGC) to
regulate production of cGMP from GTP.
• CO modulates the effect of NO by competing for binding
to the heme in sGC.
• NO and CO function as co neurotransmitters.
Carbon monoxide
66. • H2S is formed from cysteine by cystathionine β -synthase (CBS).
• CBS is activated by stimulation of ionotropic glutamate receptors
in the presence of extracellular Ca ions.
• H2S at physiologic concentrations facilitates the induction of long-
term potentiation (LTP) in the hippocampus.
Hydrogen sulfide
67.
68. • D amino acids were unknown in mammalian brain, so it
was thought to be an evolutionary.
• Levels of D-serine have marked variations in different
regions of the brain, with highest concentrations in the
forebrain, where NMDA type glutamate receptors are
enriched.
D serine
69. • It is proposed that synaptic release of glutamate from a
presynaptic neuron triggers the release of D-serine from adjacent
astrocytes to coactivate the NMDA receptors on nearby
postsynaptic neurons.
• D serine is synthesized from L serine by an enzyme serine
racemase.
• D serine fulfils some criteria for neurotransmitter but its
localization in glia was somewhat discomforting to
neuroscientists.
70. • The psychotic state after administration of NMDA antagonists
such as phencyclidine (PCP) closely resembles certain features of
schizophrenia, more than most drug psychoses.
• According to the NMDA receptor model of schizophrenia, one
would expect glutamate agonists to be therapeutic.
• D serine has been added to glutamate agonist to lessen the
neurotoxicity of glutamate and it has been found to be potentially
rewarding.
71. • Whether or not D-serine, NO, CO, or H2S satisfy all criteria for
neurotransmitter status, they certainly play important roles in
signalling in the nervous system
• None are stored in synaptic vesicles
• All the gases does not bind to the receptor, rather they diffuse out
from one neuron to enter in the other
• D-serine is found in the glial cells and not in neurons
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