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Neurotransmitters

Neurotransmitters. CRITERIA. NT found in axon terminals NT released by action potentials Synthesis identified External application mimic normal Response Pharmacology same for normal and externally applied NT ~. Lock & Key Model. NT binds to receptor NT = key Receptor = lock

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Neurotransmitters

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  1. Neurotransmitters

  2. CRITERIA • NT found in axon terminals • NT released by action potentials • Synthesis identified • External application mimic normal Response • Pharmacology same for normal and externally applied NT ~

  3. Lock & Key Model • NT binds to receptor NT = key Receptor = lock • Receptor changes shape determines if EPSP or IPSP receptor subtypes • NOT NT ~

  4. NT Receptor A • ligand binds to receptor • activation: + or - ~

  5. NT Receptor A Receptor B • Same NT can bind to different -R • different part of NT ~

  6. NT Receptor A Receptor B Specificity of drugs Drug B Drug A

  7. Acetylcholine - ACh • Most abundant NT in Peripheral N.S. • also found in Central N.S. • Precursor = choline nutrient • Degraded by acetylcholinesterase- • AChE Membrane bound - pre- & postsynaptic • Nicotinic receptor - ionotropic • Muscarinic receptor - metabotropic ~

  8. choline acetyltransferase ACh + CoA Acetylcholine Synthesis choline + acetyl CoA

  9. Ach - Distrubution • Peripheral N.S. • Excites somatic muscle • Autonomic NS Ganglia Parasympathetic NS Neuroeffector junction • Central N.S. - widespread Hippocampus Hypothalamus ~

  10. Cholinergic Agonists • Direct • Muscarine • Nicotine • small doses • Indirect • AChE Inhibitors ~

  11. AChE inhibitors • Physostigmine • Organophosphates - irreversible • DFP (Diisopropyl Fluorophosphate) • Soman & Sarin • Malathion* • Agonist or Antagonist? indirect agonist ~

  12. Cholinergic Antagonists • Direct Nicotinic - Curare Muscarinic - Atropine Scopolamine • Indirect Botulinum Toxin Black Widow Spider Venom ~

  13. A ACh AChE Botulinum toxin BWSV curare atropine AChE N M

  14. Monamines • Amino acid precursors • single amine group • 2 groups Catecholamines - catechol ring Indolamine - indole ring • Affected by many of same drugs ~

  15. Catecholamines Dopamine - DA Dopaminergic Norepinephrine - NE Noradrenergic Epinephrine - E Adrenergic ~ Indolamines Serotonin - 5-HT Serotonergic Monoamines

  16. Monoamines • Terminated by... reuptake monoamine oxidase - MAO catechol-O-methyltranferase - COMT also in liver • Reserpine ---> leaky vesicles depletes monoamines ~

  17. Monoamines MAO Reserpine A COMT MAO

  18. Indirect Monoamine Agonists • MAOIs Iproniazid,selegiline,moclobemide • Reuptake blockers • Tricyclic antidepressants Imipramine Desipramine Cocaine & Amphetamine ~

  19. Dopamine • Only in central nervous system mostly inhibitory systems • Reward • Schizophrenia • Movement • Nigrostriatal Pathway • At least 5 DA-R types: D1, D2, etc. ~

  20. Dopaminergic Drugs • Agonist • L-dopa • Antagonists • Chlorpromazine D1 • Haloperidol D2 ~

  21. tyrosine hydroxylase DOPA decarboxylase DOPA DA Dopamine Synthesis Tyrosine

  22. Norepinephrine • Peripheral N.S. • Sympathetic neuroeffector junction • Adrenal glands • Central N.S. • Hypothalamus • Locus coeruleus • Alpha & Beta receptor subtypes • NEa & NEb ~

  23. Noradrenergic Drugs • Agonists • Mescaline • Ephedrine • Antagonist • Propranalol - • beta receptors ~

  24. Norepinephrine Synthesis tyrosine hydroxylase DOPA decarboxylase dopamine b hydroxylase DOPA DA NE Tyrosine

  25. Serotonin • NOT a catecholamine • Peripheral 98% in blood & smooth muscle • Central N.S. Raphe nucleus Hypothalamus • R subtypes: 5HT1 & 5HT2 ~

  26. Sertonergic Drugs • Agonists • SSRIs Selective Serotonin Reuptake Inhibitors (fluxoteine, sertraline, paroxetine….) • Buspirone • MDMA (3,4-methylenedioxymethamphetamine) Ecstacy ~

  27. Sertonergic Drugs • Antagonists • Psilocybin • LSD (Lysergic acid diethylamide) in CNS • Inverse agonist • ketanserin ~

  28. tryptophan hydroxylase 5-HTP decarboxylase 5-HT 5-HTP Serotonin Synthesis Tryptophan

  29. Gamma-aminobutyric acid • GABA - GABAergic • Major NT in brain inhibitory system • Receptor subtypes GABAA - controls Cl- channel GABAB - controls K+ channel • Precursor = glutamate ~

  30. GABAergic Drugs • Agonists • Benzodiazepines • Barbiturates • Ethyl alcohol (ETOH) • Antagonists Picrotoxin • Inverse agonist • Ro 15-4513 • ßCCM ~

  31. GABA Synthesis & Reuptake • From Krebs cycle metabolism of glucose in mitochondria • From Glial cells GABA ---> Glutamate ---> Glutamine Glutamine into neurons • After release GABA back into glia ~

  32. glutamic acid decarboxylase GABA Synthesis GABA Glutamate

  33. Neuropeptide • Chains of amino acids • Synthesis in soma • Often neuromodulators • alters sensitivity of neurons • slower, longer-lasting effects • Substance P - pain signaling • Endorphins - analgesia, euphoria ~

  34. Endorphins • Opioids Dynorphin met-enkephalin leu-enkephalin Beta-endorphin • Receptor subtypes: mu1, mu2, kappa, delta, omega ~

  35. Endorphins (cont.) • Agonists • morphine • heroin • codeine • Antagonists • naloxone • naltrexone ~

  36. Other NTs • Excitatory amino acids • Glutamate & Aspartate • Histamine • Inflammatory Response • Nitric Oxide - It’s a gas • Carbon Monoxide? • Anandamide ligand for THC-R ~

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