Neurotransmitters

Anant Kumar Rathi

Final Year Resident, Psychiatry
Medical College, Kota (Raj.)

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

Otto Loewis Experiment -1921

This is a NEURON.
Dendrites are branching
fibers that receive
information from other
neurons

Dendrit
es

Som
a

Soma is the cell body

of a neuron. It
contains a nucleus,
ribosomes,
mitochondria, and
other structures. This
is where much of the
metabolic work takes
place

Presynaptic
terminals

Axon is a thin
fiber where
information is
sent from the
neuron to other
neurons Axon

Presynaptic
terminals are
the point where
the axon
releases
chemicals

Pre-synaptic Neuron

Neurotransmit
ters are sent
through the
axon to presynaptic
terminals, and
then to
another
neuron

Post-synaptic Neuron

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

NEUROTRANSMITTERS
Chemical transducers
released
By electrical impulse
Into the synaptic cleft
From pre-synaptic
membrane
By synaptic vesicles.

Diffuse to the postsynaptic membrane

React and activate the
receptors present
Leading to initiation of
new electrical signals.
7

Ca2+

Ca2+

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 cells
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

Excitatory neurotransmitters:

Inhibitory neurotransmitters:

Neurotransmitters in brain
AMINES
Dopamine
Serotonin
Norepinephrine
Epinephrine
Acetylcholine
Melatonin
Histamine

PITUTORY
PEPTIDES
ACTH
GH
TSH
Oxytocin
Vasopressin
Prolactin
Alpha MSH

AMINO ACIDS
Glutamic acid
GABA
Glycine
Aspartic acid

OPIOIDS
PEPTIDES
Dynorphins
Endorphin
Enkephaline

MISCELLANE
OUS
PEPTIDES
Bradykinin
Neuropeptid
eY
Neurotensin
Bombesin

CIRCULATING
HORMONES
Angiotensin
Calcitonin
Glucagon
Insulin
Estrogen
Thyroid
hormones
Cortisol

HYPOTHALAM
IC RELEASING
HORMONES
CRH
GnRH
LHRH
TRH
GHRH
Somatostatin

GASES
NO
CO
NEUROKININ
S
Substance p
LIPID NT
Anandamide
PURINES

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

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

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

Dopaminergic pathways
Mesocortical
pathway

Nigrostriatal
pathway
(part of EP system)

Mesolimbic
pathway
Tuberoinfundibular pathway
(inhibits prolactin release)

Adapted from Inoue and Nakata. Jpn J Pharmacol. 2001;86:376.

Dopaminergic Pathways

18
Moore et al. 1978

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

Dopamine hypothesis of
schizophrenia

Parkinsons 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

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
22
extracellular space

Nor-epinephrine

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

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)

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

(Rate
limiting)

COOH
C NH2

OH

Tryptophan
hydroxylase

NH2

Active
TryptophanInCNSdiet.
transport

C
N

COOH

5-Hydroxytryptophan
5-OH Tryptophan
decarboxylase

COOH

de Ald
hy eh
dr yd
og e
en
as
e

5-Hydroxy Indole
Acetic Acid

OH

H
C

AO
M

5-OH Indole
Acetaldehyde

NH2

5-Hydroxytryptamine

 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

Amine Neurotransmitters

Many antidepressants are specific to this NT

SSRIs
Block reuptake of 5HT in the synapse

It can be excitatory or
inhibitory

CHOLINERGIC NEURON

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

Ach Alzheimer's disease

 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.

MELATONIN
Melatonin is produced by thepineal gland, a
small endocrine gland located in the center
of the brain but outside the bloodbrain
barrier
Regulates thesleep-wake cycle paracrine
effect SCN
Antioxidant
Immune system
Autism
Parkinson's disease

GLUTAMATE

GABA

 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.

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.

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.

Brain Derived Neurotrophic Factor

(BDNF)
Protein is coded by the BDNF gene located
onchromosome 11
It is active in the hippocampus, cortex andbasal forebrain
areas vital to learning, memory, and higher thinking.
BDNF itself is important forlong-term memory
Help to support the survival of existing neurons, and
encourage the growth and differentiation of new neurons
andsynapses
Various studies have shown possible links between BDNF
and conditions such
asdepression,schizophrenia,obsessive-compulsive
disorder,Alzheimer's disease,Huntington's disease,Rett
syndrome,anddementiaas well asanorexia
nervosaandbulimia nervosa

BDNF & Depression

Exposure tostressand the stress
hormonecorticosteronehas been shown to decrease
theexpression 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
chronicdepression
Excitatory neurotransmitterglutamate,
voluntaryexercise,caloric restriction, intellectual
stimulation,curcuminand various treatments for
depression antidepressantsandelectroconvulsive
therapyandsleep deprivationincrease expression of BDNF
in the brain.

Alzheimers disease
Post mortem analysis has shown lowered levels of BDNF in
the brain tissues of people withAlzheimer's disease
Neurotrophic factors have a protective role againstamyloid
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

 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 GABAAreceptor-mediated post-synaptic currents

Glial cell line Derived Neurotrophic

Factor (GDNF) family of ligands
Fourneurotrophic 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 ofdopaminergic
neuronsin culture, and was able to
preventapoptosisof motor neurons

 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 Parkinsons disease therapy

and forepilepsytreatment
NRTN promotes survival of basal forebrain cholinergic
neuronsand spinal motor neurons. Therefore, NRTN has
a potential in the treatment of Alzheimers 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 Alzheimers
disease & stroke.

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.

 Human body produces at least 20 different

endorphins
alpha () endorphin
beta () endorphin - Most powerful
gamma () endorphin
sigma () endorphin

Environmental
Step 1: Cue perceived by
Central Nervous
CNS
Cue
System
Stressor
Step 2: Signal sent to
( pain)
hypothalamus (in
brain)
Hypothalamus
Corticotropin releasing factor
Step 3: Hypothalamus
(CRF)
secretes CRF (peptide),
travels to pituitary

Anterior Pituitary

Brai
n

Pro-Opiomelanocortin
(POMC)
age)
v
a
e
l
c
atic
m
y
z
n
e
(

Beta-lipotropin

Endorphin Hormone
(EP)

Step 4: CRF causes

protein
proOpiomelanocortin
hormone (POMC) to be
cleaved, releases Beta
lipotropin
Step 5: lipotropin gets
convert
into Endorphin.
Step 6:
binds to

Endorphin

TRANSPORT AND DISTRIBUTION

-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 contacts with
target neurones to reduce pain.
Free hormones are rapidly
eliminated
from circulation through

Hypothalamus

FUNCTION AS ANALGESIC
PAIN IMPULSE STOP BY ENDORPHIN : MECHANISM
After endorphin
release

hypothalam
hypothalam
us
us

Before endorphin
release

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.
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

Heroin addiction

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.