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Brain Neurotransmitters

Brain Neurotransmitters. Dr. Taha Sadig Ahmed, Physiology Department , College of Medicine , King Saud University , Riyadh. Acetylcholine ( ACh ). In the brain , cholinergic ( ACh producing ) neurons are present mainly in 2 areas . (1) B asal Forebrain ( namely

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Brain Neurotransmitters

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

  2. Acetylcholine (ACh)

  3. 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 ( see Brainstem Bulboreticular Facilitatory Area in Consciousness & Sleep lectures ) .

  4. Functions :The brain Cholinergic system is concerned with  • (1) Consciousness/wakefulness/alertness • (see Brainstem BulboreticularFacilitatory 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

  5. 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 CholineAcetyltransferase. • After being released into the synaptic cleft , AChibinds to its receptor & opens sodium channels  depolariztion • It is then rapidly hydrolyzed by the enzyme Actylcholinesterase into Choline and Acetate

  6. Norepinephrine& Epinephrine (Noradrenaline & Adrenaline)

  7. 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 .

  8. 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 .

  9. 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 .

  10. Tyrosine Tyrosine Hydroxylase Raete-limiting enzyme DOPA DopaDecarboxylase Dopamine (DA) Dopamine Hydroxylase Norepinephrine (NE) PNMT Epinephrine

  11. Catecholamine Catabolism/Inactivation • (1) Re-uptake into the • presynaptic neuron • where it is degraded • intracellularlyMonoamineOxidase • (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 impotrant for removal of catecholamines than mechanism 2

  12. 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

  13. Dopamine(DA)

  14. Tyrosine Tyrosine Hydroxylase Dopa Dopa Decarboxylase Dopamine (DA) 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 .

  15. 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 ).

  16. Glutamate

  17. 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 .

  18. GABA

  19. 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 .

  20. 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

  21. Serotonin

  22. Too much serotonin activity  can lead to Hallucinations ( e.g., hallucinogenic drugs) • 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 MonoaminoOxidase (MAO) • Function : improved mood & decrease appetite . • Deficiency of serotonin  depression • Antidepressant drugs include  • (1) Drugs that inhibit MAO ( MonamineOxidase 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 .

  23. Glycine • In the CNS , especially spinal cord , glycine is Inhibitory neurotransmitter  by opening Chloride channels  IPSP (hyperpolarization)

  24. Opioid Peptides

  25. Opium ألأفيون is 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

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