brain neurotransmitters dr. taha sadig ahmed, physiology department, college of medicine, king saud...
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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-MesencephalicCholinergic Complex
( 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 nerve-ending & 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 itsreceptor & opens sodium channels depolariztion
It is then rapidly hydrolyzed by the enzyme Actylcholinesterase into Choline and Acetate
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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 .
• 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 beta-Hydroxylase , 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 control of the synthesis process . 8
• 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
DOPA
Dopamine (DA)
Norepinephrine (NE)
Epinephrine
Tyrosine Hydroxylase
Dopa Decarboxylase
Dopamine Hydroxylase
PNMT
Raete-limiting enzyme
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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 impotrant for removal of catecholamines than mechanism 2
(1) Re-uptake into the presynaptic neuron where it is degradedintracellularly MonoamineOxidase(MAO) enzyme;
(2) Extracellular inactivation byCatechol-O-Methyl Transferase (COMT)
Catecholamine Catabolism/Inactivation
• Functions : of the Brain NE System • (1) It constitutes part of the RAS ( Reticualr
Activating Systemalertness ) + 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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Tyrosine
Dopa
Dopamine (DA)
Tyrosine Hydroxylase
Dopa Decarboxylase
• 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 .
• 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 .19
• 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 anti-anxiety effect ; and are effective (2) muscle relaxants , (3) anticonvulsants , and (4) sedatives
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Serotonin
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• Serotonin is formed by the hydroxylation & decarboxylation of tryptophan , whose neuronal cell bodies are present in Raphe 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 as Prozac (Fluoxetine ) are also effective antidepressants These are called SSRIs (serotonin-specific reuptake inhibitors) which inhibit reuptake and destruction of serotonin & thereby prolong its action. .
• SSRI also improve mood• ( reduce anxiety ) and
decrease appetite .
Too much serotonin activity can lead to Hallucinations ( e.g., hallucinogenic drugs)
Glycine
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• In the CNS , especially spinal cord , glycine is Inhibitory neurotransmitter by opening Chloride channels IPSP (hyperpolarization)
Opioid Peptides
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• Opium أألفيون is a plant that was known from the dawn of history , Morphine is a drug derived fromopium . 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 aremedaited by opioid receptors within thebody
Opium Puppy