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Brain
Neurotransmitters
Dr. Taha Sadig Ahmed,
Physiology Department , College of Medicine , King
Saud University , Riyadh
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Acetylcholine
(ACh)
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In the brain , cholinergic ( ACh producing )
neurons are present mainly in 2 areas 
(1) Basal Forebrain ( namely
Nucleus Basalis of Myenert )
(2)Ponto-Mesencephalic
Cholinergic Complex
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( see Brainstem Bulboreticular Facilitatory
Area in Consciousness & Sleep lectures ) .
• Functions :The brain Cholinergic system
is concerned with 
• (1) Consciousness/wakefulness/alertness
•
(see Brainstem Bulboreticular Facilitatory Area
in Consciousness & Sleep lectures ) .
• (2) Memory & learning .
• Defects in the brain cholinergic system interfere with
learning and memory , such as in Alzheimer’s disease
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• ACh is synthesized at the nerveending & synthesis involves the
reaction of Choline & Active acetate
(Acetyl-CoA , Acetylcoenzyme A)
• Cholinergic neurons actively take up
choline via a transporter
• The acetate is activated to become
Acetyl-coenzyme A ( Acetyl-CoA), &
then Acetyl-CoA reacts with choline
to form ACh
• This reaction is catalyzed by the
enzyme Choline Acetyltransferase .
After being released into the
synaptic cleft , ACh ibinds to its
receptor & opens sodium channels
 depolariztion
It is then rapidly hydrolyzed by the
enzyme Actylcholinesterase
into Choline and Acetate
Norepinephrine
& Epinephrine
(Noradrenaline & Adrenaline)
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• The cell-bodies of Norepinephrine neurons are located in
mainly Locus Cereulus
• From Locus Cereulus the axons of noradrenergic neurons arborize
widely in the brain , constituting the Locus Cereulus System .
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• The three Catecholamines ( dopamine , NE and epinephrine
) are formed by hydroxylation and decarboxylation of the
amino acid Tyrosine .
• Tyrosine is converted to Dopa and then Dopamine in the
cytoplasm of cells by Tyrosine Hydroxylase and Dopa
Decarboxylase
• The Dopamine then enters the granulated vesicles , and
inside them it is converted to Norepinephrine by the
enzyme Dopamine Hydroxylase ( Dopamine betaHydroxylase , DBH)
• L-Dopa is the isomer of Dopamine .
• Tyrosine Hydroxylase is the rate-limiting enzyme of
synthesis , & it is subject to feed-back inhibition by
dopamine and norepinephrine , thus prividing internal
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control of the synthesis process
.
• Some brain neurons and adrenal medullary cells ( but
not postganglionic sympathetic nerves ) contain the
their cytoplasm the enzyme PNMT (
Phenylthanolamine-N-Methyl Transferase ) , which
converts norepinephrine into epinephrine .
• In these epinephrine-secreting neurons ,
norepinephrine leaves the vesicles to the cytoplasm ,
where it is converted by PNMT into epinephrine , and
then enters other storage vesicles .
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Tyrosine
Tyrosine
Hydroxylase
Raete-limiting
enzyme
DOPA
Dopa
Decarboxylase
Dopamine (DA)
Dopamine
Hydroxylase
Norepinephrine (NE)
PNMT
Epinephrine

Catecholamine Catabolism/Inactivation
(1) Re-uptake into the
presynaptic neuron
 where it is degraded
intracellularly MonoamineOxidase
(MAO) enzyme;

(2) Extracellular inactivation by
Catechol-O-Methyl Transferase
(COMT)



COMTis actually attached extracellularly to the
postsynaptic membrane  therefore it is also correct to
say that Catecholamines are degraded on the Postsynaptic
membrane .
Reuptake & degradation by MAO ( mechanism 1 ) is more
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impotrant for removal of catecholamines than mechanism 2
• Functions : of the Brain NE System
• (1) It constitutes part of the RAS ( Reticualr
Activating Systemalertness ) + plays role in 
• (2) fight-flight situations , including competitive
athletic behavior &
• (3) aggressive behavior .
• Deficiency of Norepinephrine or Serotonin 
Depression
Dopamine
(DA)
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• In certain parts of the
brain , catecholamine
synthesis stops at
dopamine ( DA) .
• Like other catecholamines ,
after being secreted into
the synaptic cleft , DA is
either reuptaken into the
presynaptic membrane &
inactivated intracellularly
by MAO ( main way of
removal from synaptic
cleft) , or removed from
the cleft by the action of
COMT on it .
Tyrosine
Tyrosine
Hydroxylase
Dopa
Dopa
Decarboxylase
Dopamine (DA)
• In the brain , dopaminergic neurons
comprise 
• (A) Nigrostriatal System :
• Dopaminergic fibers originate in
Substantia Nigra and project to the
Striatum .
• This system is involved in motor
control , & DA deficiency in Basal
Ganglia  Parkinsonism
• (B) Mesocortical System :
• Arises from the Ventral Tegmental
Area ( VTA) , and projects to Nucleus
Accumbens and Limbic System .
• The Mesocortical System is involved
in behaviors of Pleasure , Reward ,
and Addiction
• Mesocortical System overstimulation
can lead to  (1) Schizophrenia-like
symptomsor & to (2) Addiction ( if
stimulated by a narcotic drug ).
Glutamate
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In Health : •
• (1) Glutamic acid (and aspartic acid) : are major
excitatory NTs in CNS.
• (2) Glutamate NMDA receptor involved in Long-Term
Potentiation & memory storage.
• In Disease :
• (1) Excess Glutamate activity is implicated in some
types of epileptic seizures
• (2) Under some pathological conditions , such Stroke ,
ALS (Amyotrophic Lateral Sclerosis) , and
Alzheimer's diseases, it acts as an excitotoxin 
producing exceesive influx of calcium into the neurons
 causing neuronal death .
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GABA
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• GABA is an important inhibitory transmitter in
the brain (including being responsible for
presynaptic inhibition ).
• Formation : GABA is formed by decarboxylation
of Glutamate . The enzyme which catalyzes this
reaction is Glutamic Acid Decarboxylase (GAD ,
Glutamate Decarboxylase ).
• Inactivation : by 2 ways 
• (1) GABA is metabolized by the enzyme GABA
transaminase .
• (2) In addition , there is active reuptake of
GABA via a GABA transporter . This vesicular
GABA transporter transports GABA and Glycine
into secretory vesicles .
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• Activation of GABA receptors can lead to 
• (1) increased potassium channel conductance 
potassium outflux ( efflux)  hyperpolarization
• (2) increased chloride channel conductance 
chloride influx  hyperpolarization
• (3) decreased calcium channel conductance 
inhibited calcium influx hyperpolarization
• The increase in chloride conductance produced by
GABA receptors is potentiated by the Diazepam (
Valium ) and other Benzodiazepines .
• The Benzodiazepines have (1) marked antianxiety effect ; and are effective (2)
muscle
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relaxants , (3) anticonvulsants , and (4) sedatives
Serotonin
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Too much serotonin
• Serotonin is formed by the hydroxylation
activity  can lead to
& decarboxylation of tryptophan , whose
Hallucinations ( e.g.,
neuronal cell bodies are present in Raphe
hallucinogenic drugs)
Nuclei ( that is why serotonin is present
in brain Raphe Nuclei )
• After release , it is removed from the
synaptic space by an active reuptake
mechanism . Thereafter , inside the
nerve-ending it is inactivated by the
enzyme Monoamino Oxidase (MAO)
• Function : improved mood & decrease
appetite .
• Deficiency of serotonin  depression
• Antidepressant drugs include 
• (1) Drugs that inhibit MAO ( Monamine
Oxidase Inhibitors ) ,and
• Drugs that inhibit serotonin uptake such • SSRI also improve mood
as Prozac (Fluoxetine ) are also effective
•
( reduce anxiety ) and
antidepressants These are called SSRIs
decrease appetite .
(serotonin-specific reuptake inhibitors) which inhibit
reuptake and destruction of serotonin  & thereby
Glycine
• In the CNS , especially spinal cord ,
glycine is Inhibitory neurotransmitter 
by opening Chloride channels  IPSP
(hyperpolarization)
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Opioid
Peptides
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• Opium ‫ أألفيون‬is a plant that was known
from the dawn of history ,
 Morphine is a drug derived from
opium .
 It is a powerful analgesic & euphoric
drug .
 However , if not used wisely , it can be
highly addictive
 Morphine & realted derivatives of opium
are called opiate drugs ( they are called
external opiates ) .
• Their analgesic/euphoric actions are
medaited by opioid receptors within the
body
Opium Puppy