The document discusses neurotransmitters and their roles in the nervous system. It outlines the criteria for classifying a molecule as a neurotransmitter, identifies major types of neurotransmitters including amino acids, amines, and peptides. It describes the mechanism of neurotransmitter release and action, and discusses clinical disorders that can arise from disruptions in neurotransmitter metabolism such as Parkinson's disease, schizophrenia, and addiction.

1. Neurotransmitters
Anant Kumar Rathi
Final Year Resident, Psychiatry
Medical College, Kota (Raj.)

2. Objectives
1- Outline the criteria that need to be met before a
molecule can be classified as “neurotransmitter”
2- Identify the major neurotransmitter types
3- Mechanism of action of important neurotransmitters
4- Identify some clinical disorders that can arise as a
result of disruption of neurotransmitter metabolism

3. Otto Loewi’s Experiment -1921

4. This is a NEURON. Soma is the cell body of a
neuron. It contains a
nucleus, ribosomes, mitoch
ondria, and other
Soma structures. This is where
Dendrites are branching fibers much of the metabolic
that receive information from work takes place
other neurons
Dendrites
Presynaptic
terminals
Presynaptic
Axon is a thin fiber terminals are the
where information point where the
is sent from the axon releases
neuron to other chemicals
neurons
Axon

5. Pre-synaptic Neuron
Neurotransmitters
are sent through
the axon to pre-
synaptic
terminals, and then
to another neuron
Post-synaptic Neuron

6. Summary
It travels through the axon
Neurotransmitter comes from soma
From the pre-synaptic terminal it is taken
through the synapse to the next neuron
Re-uptake sometimes occurs

7. NEUROTRANSMITTERS
Chemical transducers released
By electrical impulse
Into the synaptic cleft
From pre-synaptic membrane
By synaptic vesicles.
Diffuse to the post-synaptic
membrane
React and activate the
receptors present
Leading to initiation of new
electrical signals.

9. Ca2+ Ca2+

10. Neurotransmitter receptors
• Once released, the neurotransmitter molecules diffuse across the
synaptic cleft
• When they “arrive” at the postsynaptic membrane, they bind to
neurotransmitter receptors
• Two main classes of receptors:
– Ligand-gated ion channels
• transmitter molecules bind on the outside, cause the channel to open and become
permeable to either sodium, potassium or chloride
– G-protein-coupled receptors
• G-protein-coupled receptors have slower, longer-lasting and diverse postsynaptic
effects. They can have effects that change an entire cell’s metabolism
• or an enzyme that activates an internal metabolic change inside the cell
• activate cAMP
• activate cellular genes: forms more receptor proteins
• activate protein kinase: decrease the number of proteins

11. Excitatory neurotransmitters:

12. Inhibitory neurotransmitters:

13. Neurotransmitters in brain
AMINES
Dopamine
MISCELLANEOUS
Serotonin AMINO ACIDS
OPIOIDS PEPTIDES PEPTIDES
Nor-epinephrine Glutamic acid
Dynorphins Bradykinin
Epinephrine GABA
Endorphin Neuropeptide Y
Acetylcholine Glycine
Enkephaline Neurotensin
Melatonin Aspartic acid
Bombesin
Histamine
CIRCULATING HYPOTHALAMIC
PITUTORY PEPTIDES GASES
HORMONES RELEASING
ACTH NO
Angiotensin HORMONES
GH CO
Calcitonin CRH
TSH NEUROKININS
Glucagon GnRH
Oxytocin Substance p
Insulin LHRH
Vasopressin LIPID NT
Estrogen TRH
Prolactin Anandamide
Thyroid hormones GHRH
Alpha MSH PURINES
Cortisol Somatostatin

14. Neuromodulators
• Neurotransmitters transmit an impulse from one
neuron to another
• Neuromodulator modulate regions or circuits of the
brain
• They affect a group of neurons, causing a modulation
of that group
• Neuromodulators alter neuronal activity by
amplifying or dampening synaptic activity
– eg.
dopamine, serotonin, acetylcholine, histamine, glutamate

15. Dopamine - as NT by Arvid Carlsson 1958
• DOPA is converted so
rapidly into Dopamine
that DOPA levels are
negligible in the brain
• Rate of synthesis is
regulated by
– Catecholamine acting as
inhibitor of TH
– Availability of BH4
– Presynaptic DA receptors
– Amount of activity in
nigrostriatal pathway

16. Metabolism
• In rats – DOPAC major
metabolite
• In primates and human
– HVA major metabolite
• Accumulation of HVA in
brain or CSF used as
index of function of
dopaminergic neurons

17. Dopaminergic pathways
Mesocortical Nigrostriatal
pathway pathway
(part of EP system)
Mesolimbic
pathway
Tuberoinfundibular pathway
(inhibits prolactin release)
Adapted from Inoue and Nakata. Jpn J Pharmacol. 2001;86:376.

18. Dopaminergic Pathways
18
Moore et al. 1978

19. Significance of Dopaminergic Pathways
• Mesolimbic Pathway
– Associated with pleasure, reward and goal directed
behavior
• Mesocortical Pathway
– Associated with motivational and emotional responses
• Nigrostriatal Pathway
– Involved in coordination of movement (part of basal
ganglia motor loop)
• Tuberoinfundibular Pathway
– Regulates secretion of prolactin by pituitary gland and
involved in maternal behavior
19

20. Dopamine hypothesis of schizophrenia

21. Parkinson’s Disease
• Substantial loss of Dopamine
in the striatum (70 – 80%)
• Loss of dopamine neurons in
other systems also
(mesolimbic, mesocortical and
hypothalamic systems)
• Treatment strategy includes
increasing dopamine levels by
administering L-Dopa, nerve
grafting with dopamine
containing cells and deep brain
stimulation
21

22. Dopamine and Addiction
• The dopaminergic projection to ventral striatum has often
been implicated in the mechanisms for addiction
• Increased loco motor activity and stereotypy caused due to
psycho stimulant involve dopamine release in striatum
• Cocaine binds to DAT (at a different site) preventing the
reuptake of dopamine by the cells leading to an increased
extracellular levels of dopamine
• Amphetamine acts as a false substrate and is transported into
the cytoplasm and results in reverse transport of dopamine
from cytoplasm to the extracellular space
22

23. Nor-epinephrine

24. Norepinephrine or NE
• In the CNS, norepinephrine is used by neurons of the locus
coeruleus, a nucleus of the brainstem with complex modulator
functions
• In the peripheral nervous system, norepinephrine is the transmitter
of the sympathetic nervous system
• Involved in sleep, wakefulness, attention and feeding behavior
• At least two kinds of NE receptors: NE alpha and NE beta
• Indicated effects:
– primarily excitatory
– appears to modulate Fear/flight/fight system
• Too much: over arousal, mania
• Too little: under arousal, depression
– Chemically extremely similar to Dopamine, serotonin

26. Removal of Catecholamines
• All three catecholamines are removed
by selective reuptake by the presynaptic
axon terminals
• They are either reused or degraded by
monoamine oxidase (MAO)

27. Serotonin
Secreted by the nuclei originating in the median raphe of the
brain stem and terminate in dorsal horn of the spinal cord and
hypothalamus

28. (Rate limiting) OH
COOH COOH
Tryptophan
C NH2 hydroxylase C NH2
N N
In diet. Active
Tryptophan CNS transport 5-Hydroxytryptophan
5-OH Tryptophan
decarboxylase
C COOH
OH H
N
C NH2
5-Hydroxy Indole N
Acetic Acid 5-OH Indole
Acetaldehyde 5-Hydroxytryptamine

29. • Excitatory & Inhibitory
• Control the mood of the person and important in sleep
• Also present in GIT, platelets & limbic system
• Receptors: 1A, 1B, 1D, 2A, 2C, 3, 4, 5, 6, 7
• Low levels are associated with depression and other
psychiatric disorders
• May be involved in migraine

32. Amine Neurotransmitters

33. Many antidepressants are specific to this NT
SSRI’s
Block reuptake of 5HT in the synapse

35. CHOLINERGIC NEURON
It can be excitatory or inhibitory

36. Cholinergic receptors
• Two kinds of receptors
– Nicotinic
• Nicotine stimulates
• Excitatory; found predominately on neuromuscular junctions
– Muscarinic
• Muscarine (mushroom derivative) stimulates
• Both excitatory AND Inhibitory; found predominately in brain
• Indicated effects:
– excitation or inhibition of target organs
– essential in movement of muscles
– important in learning and memory

37. Ach – Alzheimer's disease

38.  Cholinergic neurons have interactions with all three
monoamine systems.
 Agonist can produce lethargy, anergia and
psychomotor retardation in normal subjects.
-can exacerbate symptoms in depression
-can reduce symptoms in mania.

39. MELATONIN
• Melatonin is produced by the pineal gland, a small
endocrine gland located in the center of the brain
but outside the blood–brain barrier
• Regulates the sleep-wake cycle paracrine effect –
SCN
• Antioxidant
• Immune system
• Autism
• Parkinson's disease

40. GLUTAMATE

51. GABA

53. • Decreased GABA-A receptor binding in a
positron emission tomography (PET) study of
patients with panic disorder.
• Low plasma GABA has been reported in some
depressed patients and, in fact, may be a
useful trait marker for mood disorders.

54. HPA axis (hypothalamo-pituitary-adrenal axis)
 Elevated HPA activity is a hallmark of mammalian stress responses
and one of the clearest links between depression and biology of
chronic stress.
 50% of depressed patients have elevated cortisol level
(resolves with treatment --- persistently increased level indicate a
high risk of relapse )
 CRH levels are also elevated in CSF of depressed pts.
(Central CRH receptor antagonists-possible antidepressants)
 Elevated HPA activity in depression has been documented via
Dexamethasone Suppression Test.
Nonsuppresion may implicate a loss of inhibitory hippocampal
glucocorticoid receptors resulting in increased CRH drive.

55. Thyroid axis -
 Disturbed in about 5 to 10% of persons with
depression
 About 1/3rd of pts have blunted TSH response to iv
TRH
 10% of pts may have circulating antithyroid
antibodies
 CSF somatostatin levels  decreased in depression,
and increased in mania.

56. Brain Derived Neurotrophic Factor (BDNF)
• Protein is coded by the BDNF gene located on chromosome 11
• It is active in the hippocampus, cortex and basal forebrain—areas
vital to learning, memory, and higher thinking.
• BDNF itself is important for long-term memory
• Help to support the survival of existing neurons, and encourage
the growth and differentiation of new neurons and synapses
• Various studies have shown possible links between BDNF and
conditions such as depression, schizophrenia, obsessive-
compulsive disorder, Alzheimer's disease, Huntington's
disease, Rett syndrome, and dementia as well as anorexia
nervosa and bulimia nervosa

57. BDNF & Depression
• Exposure to stress and the stress hormone corticosterone has
been shown to decrease the expression of BDNF in rats
• If exposure is persistent, this leads to an eventual atrophy of the
hippocampus.
• Atrophy of the hippocampus and other limbic structures has
been shown to take place in humans suffering from
chronic depression
• Excitatory neurotransmitter glutamate, voluntary exercise, caloric
restriction, intellectual stimulation, curcumin and various
treatments for depression antidepressants and electroconvulsive
therapy and sleep deprivation increase expression of BDNF in the
brain.

58. Alzheimer’s disease
• Post mortem analysis has shown lowered levels of BDNF in the
brain tissues of people with Alzheimer's disease
• Neurotrophic factors have a protective role against amyloid beta
toxicity
• A connection between depression and dementia has been
suggested to be mediated by BDNF
• Depression causes shrinkage of the hippocampus. When
antidepressants are administered, the levels of BDNF are raised to
protect and increase the volume of hippocampal and other cells
• In Alzheimer's, the hippocampus is also damaged, lowering levels of
the neurotrophic factor
• Another possible link between BDNF and dementia is through
fitness, since exercise can release BDNF and preserve cognition in
older people

59. • Drug dependency - Animals chronically exposed to
drugs of abuse show increased levels of BDNF in the
ventral tegmental area (VTA) of the brain
• When BDNF is injected directly into the VTA of
rats, the animals act as if they are dependent on
opiates
• Epilepsy - levels of both BDNF mRNA and BDNF
protein are known to be up-regulated in epilepsy
• BDNF modulates excitatory and inhibitory synaptic
transmission by inhibiting GABAA-receptor-mediated
post-synaptic currents

60. Glial cell line Derived Neurotrophic Factor
(GDNF) family of ligands
• Four neurotrophic factors:
– Glial cell line-derived neurotrophic factor (GDNF),
– Neurturin (NRTN),
– Artemin (ARTN)
– Persephin (PSPN)
• Play a role in cell survival, neurite outgrowth, cell
differentiation and cell migration
• In particular signaling by GDNF promote the
survival and differentiation of dopaminergic
neurons in culture, and was able to
prevent apoptosis of motor neurons

61. • GDNF has shown promising results in
– Parkinson's disease
– Amytrophic Lateral Sclerosis
– Recent results- drug addiction and alcoholism treatment
• NRTN can also be used for Parkinson’s disease therapy and
for epilepsy treatment
• NRTN promotes survival of basal forebrain cholinergic
neurons and spinal motor neurons. Therefore, NRTN has a
potential in the treatment of Alzheimer’s disease and ALS
• ARTN also has a therapeutic perspective, for it is considered
for chronic pain treatment
• PSPN may be used for the treatment of Alzheimer’s disease
& stroke.

62. Endorphins - endogenous morphine
• A peptide hormone named Endorphin produced in
the brain and anterior pituitary
• High concentrations of endorphins in the brain
produce a sense of euphoria, enhance pleasure, and
suppress pain, both emotionally and physically.
• Low concentrations of endorphins in the brain
people feel anxious and they are also more aware of
pain.

63. • Human body produces at least 20 different
endorphins
• alpha (α) endorphin
• beta (β) endorphin - Most powerful
• gamma (γ) endorphin
• sigma (σ) endorphin

64. Environmental •Step 1: Cue perceived by CNS
Cue Central Nervous
“Stressor” System •Step 2: Signal sent to
hypothalamus (in brain)
( pain)
Hypothalamus •Step 3: Hypothalamus
secretes CRF
Corticotropin releasing factor
(peptide), travels to
(CRF) pituitary
•Step 4: CRF causes protein pro-
Anterior Pituitary Opiomelanocortin hormone
Pro-Opiomelanocortin (POMC) to be cleaved, releases
Brain
Beta lipotropin
(POMC)
•Step 5: lipotropin gets convert
into Endorphin.
Beta-lipotropin
•Step 6: Endorphin binds to
the nerve fiber.
Endorphin Hormone
(EP)

65. TRANSPORT AND DISTRIBUTION
 β-endorphin is released by :
1. Pituitary (into blood ) and
2. Hypothalamus ( into the spinal
cord and brain )
 Beta endorphin containing nerve
fibres spread widely from
neurones in the
hypothalamus, to make inhibitory Hypothalamus
contacts with target neurones to
reduce pain.
Free hormones are rapidly eliminated
from circulation through
kidney or liver.

66. FUNCTION AS ANALGESIC
PAIN IMPULSE STOP BY ENDORPHIN : MECHANISM
Before endorphin release After endorphin release
hypothalamus

67. WHAT IS DRUG ADDICTION ?
In the normal course Opiate
Receptors and Endorphins are
kept in balance with one another.
When the brain is flooded with
exogenous opiates, (heroin a
morphine derivative) it mimic of
endorphins so system gets
confused. Heroin addiction
It thinks it is making too many
endorphins and shuts that
down, But it still has all this excess
(heroin) and thinks that it also
needs to make more receptors.

68. What Happens Next….
• As more Opiate Receptors are
made you need more heroin to
get the same effect so you use
more.
• And more receptors are made to
accommodate the extra what the
brain thinks is endorphins.
• For decreasing this effect- You
need more substance to get the
same effect.