Brain Neurotransmitters Dr. Taha Sadig Ahmed, Physiology Department, College of Medicine, King Saud University, Riyadh 1.

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