NEUROTRANSMITTERS

DEFINITION:

Neurotransmitters are the chemical

substances liberated at the nerve
endings and help to transfer the
message of the nerve impulses in the
presynaptic neuron to an adjacent
cell ( Eg: Postsynaptic neuron,
muscle or to a gland)
 Chemical Substances
I) Biogenic amines: Catecholamines
a) Epinephrine
b) Nor epinephrine
c) Dopamine
Histamine
Serotonin

II) Peptides: Enkephalins

Substance P
Somatostatin
III) Amino acids: GABA, Glycine, Asp, Glu

IV) Acetyl choline, ATP, NO, Co

 Acetyl Choline
 Found in various synapses in brain,
parasympathetic NS, Parts of sympathetic NS,
neuromuscular junction

 ACh is synthesised by acetylation of choline

in presynaptic ending
Structure of ACh
Synthesis of Ach :

Choline + Acetyl CoA Acetyl choline

Choline acyl
+ coA
transferase
 Degradation of ACh:

Acetyl Choline Choline +

Acetyl choline Acetate
esterase
 Synthesis of Ach:

 From metabolism
CoA, NAD, FAD
Pyruvate Acetyl CoA
PDH
 Synthesis of Choline:
 Synthesized – Serine

PLP
Serine Ethanolamine
Co2

 Dietary sources: Milk, egg, liver, cereals etc..

Functions of Ach:
 Transmitter between nerves and muscles;
involved in mobility
 Involved in alertness, arousal, learning,
and memory
 Prevents fatty build-up in the liver
 Maintains flexibility of cell membrane
Ach Receptors :

 Nicotinic receptors: Ionotropic receptors

 Fast acting receptors
 Composed of 2α,β,γ,δ
 Stimulated by nicotine and Ach
 Muscle endplate, sympathetic and
parasympathetic NS and in the CNS
The structure of the nACh receptor
 Muscarinic receptors : Metabotropic
receptors
 Slow acting receptors
 Stimulated by muscarine (amanita muscaria)
and acetylcholine
 Blocked by atropine (atropa belladonna)
 Found in both CNS, peripheral nervous
system, in heart, lungs , upper GI tract and
sweat glands
 5 subunits—M1 – M5
Structure and function of metabotropic
receptor
Interesting facts:
Succinyl choline
 Structure analogue of ACh
 Post synaptic receptors for Ach competitively blocked by
Succinyl choline
 Used as a muscle relaxant during surgery

Damage to cholinergic system (BRAIN)

 Lack of acetylcholine involved in Alzheimer’s disease

Myasthenia gravis:
Acetyl choline receptors are  in Myasthenia
gravis
 This is crippling disease of muscle
 Occurs due to formation of antibodies
against ACh receptors and subsequent
destruction of ACh receptors
 Neuromuscular transmission fails – Muscle
contraction is affecting
Organophosphorus poisoning:

 These are a heterogeneous group of

compounds- composed of a phosphoric
acid derivative with two organic side
chains and an additional side chain
(cyanide, thiocyanate, halide, phosphate,
phenoxy, thiphenoxy or carboxylate
group)
 Organophosphate

O
II
R1
P-O-X
R2

R1,2 = alkyl or aryl groups

X = wide range of
branched or
substituted groups
 OPP compounds are irreversible inhibitors of AchE
Eg : Diflos

 Organophosphates inhibits acetylcholine esterase in

the nervous system

 Accumulation of acetyl choline at the synapses

 Overabundance of acetylcholine initially excites and

then paralyzes transmission in cholinergic synapses

Clinical Effects:
 Initial phase: Excessive salivation,
lacrimation, and weakness
 CNS effects: Anxiety, restlessness, coma and

seizures

Diagnosis:

Depressed serum or RBC cholinesterase level

is helpful in diagnosis
25% or greater depression of the RBC
cholinesterase level is a true indicator of poisoning
 CATECHOLAMINES
 Catechol means dihydroxylated phenyl
ring
OH
OH
 Amine derivatives of catechol are called
catecholamines

 Principle catecholamines found in the

body are
i) Dopamine
ii) Norepinephrine (Noradrenaline)
iii) Epinephrine (Adrenaline)
 Synthesis of catecholamines:

Tyrosine is precursor amino acid for synthesis

of catecholamine

 Dopamine: Substantia nigra (midbrain)

Norepinephrine: Adrenalmedulla
Midbrain tegmental areas
 CH2CHCOOH

HO NH2
O2
Tyrosine
H4- Biopterin
Tyrosine hydroxylase
H2- Biopterin
H20
HO CH2CHCOOH

HO NH2

Dihydroxy phenylalanine
(DOPA)
 PLP
Amino acid decarboxylase
CO2

HO
CH2CH2NH2

HO Dopamine
O2
Ascorbate
Dopamine β-hydroxylase
Dehydroascorbate

H2 O
HO CHCH2NH2

HO OH
Norepinephrine
S-Adenosyl
methionine Phenylethanolamine-
N-methyltransferase
S-Adenosyl
homocysteine

HO CHCH2NHCH3

HO OH
Epinephrine
 Catabolism of Dopamine
Dopamine
COMT MAO

3- Methoxydopamine Dihydroxyphenyl acetic acid

MAO COMT

Homovanillic acid

MAO = Monoaminoxidase
COMT = Catechol-O-methyl transferase
 Catabolism of Norepinephrine

MAO
Norepinephrine 3,4 dihydroxy
mandelic aldehyde
COMT

Normetanephrine COMT
Epinephrine
COMT
MAO
Metanephrine
Vanillylmandelic
acid
MAO = Monoaminoxidase
COMT = Catechol-O-methyl transferase
 Adrenoreceptors
α1
 α-adrenergic receptors
α2

β1

 β-adrenergic receptors
β2
 Dopamine receptors : (Dopaminergic)
D1--- D1- D5 ↑c-AMP

D2 --- D2, D3 and D4 - c-AMP

Mechanism of Action
 Functions of Catecholamines
 Excitatory and inhibitory Neurotransmitters
 Excitatory effects:
- Smooth muscle cells of the vessels
- ↑heart rate

Inhibitory effects :
- Bronchial tree of the lungs
- Vessels that supply blood to skeletal
muscle
●+ degradation of TAG and glycogen

●Regulate carbohydrate and lipid

metabolism

●↑BP
●+ insulin secretion
● Dopamine - limbic system of the brain
are involved in emotional responses and
memory
●Contributes - movement control
 Therapeutic applications
 β-blockers – Atenolol
- Antagonise the stimulatory effects of
catecholamines on the heart
- Used to treat hypertension and chest
pain in ischaemic heart disease
● β2- receptor agonist eg- Salbutamol
stimulates β- receptors of lungs -- to
produce bronchial dilation in asthama
without stimulating β1- receptors in the
heart
 Parkinson’s Disease
 The most common movement disorder
affecting 1-2 % of the general population
over the age of 65 years.

 The second most common neurodegenerative

disorder after Alzheimer´s disease (AD).
 ↓ production of dopamine
 Clinical features of PD
Three cardinal
symptoms:
 resting tremor
 bradykinesia
(generalized
slowness of
movements)
 muscle rigidity
 Additional clinical features of PD
 Postural instability: Due to loss of postural
reflexes.

 Dysfunction of the autonomic nervous system:

Impaired gastrointestinal motility, bladder
dysfunction, sialorrhea, excessive head and
neck sweating.

 Depression: Mild to moderate depression in

50 % of patients.
 Treatment in Parkinsonism
Blood Brain

L-DOPA L-DOPA Dopamine

HO
CH3 Blocks
HO
CH2-C-CO2 H

NHNH2

Carbidopa Dopamine

Blood Brain Barrier 43

Serotonin

H4- Biopterin

H2- Biopterin

PLP
PLP
-Trasnported by SERT

-Inactivated in presynaptic
cell by MAO and COMT

- Five 5-HT(hydroxy
tryptamine receptors)

-One ionotropic receptor

(5-HT3), the rest are
metabotropic
Catabolism of serotonin

Serotonin

MAO

5- hydroxyindole acetic 5 mg/day

acid (5-HIAA)
 Functions of serotonin
 Involved in mood, sleep, appetite and
temperature regulation
 Increases intestinal motility
 Stimulator of brains activity
 Serotonin Reserpine
↓Serotonin
MAO
+ Psychicdepressant

5- hydroxyindole acetic
acid (5-HIAA)
 Serotonin Iproniazid
↑Serotonin
MAO
_ Psychicstimulant

5- hydroxyindole acetic
acid (5-HIAA)

Iproniazid = Isopropyl isonicotinyl hydrazine

 Carcinoid tumors
 Serotonin produced by argentaffin cells of GIT
Uncontrolled growth

Malignant carcinoid

Patients complains of
Sweating
Diarrhoea
Fluctuating hypertension
 Niacin deficiency is seen

 Normally 1% tryptophan ----- serotonin

synthesis
 Carcinoid syndrome ----- 60% serotonin
synthesis
 Urinary excretion of 5 HIAA ---
500mg/day
GAMMA AMINO BUTYRIC ACID
(GABA)