Glutamate & GABA  Brian J. Piper, Ph.D.
Goals• Glutamate  – Synthesis  – Release  – Receptors (NMDA & AMPA, 1-8)  – Inactivation• GABA  – Synthesis  – Release  – ...
Terminology• Glutaminase: enzyme, converts glutamine to  glutamate• Glutamine synthetase: enzyme, converts  glutamate to g...
More Terminology• Glutamate: aka glutamic acid• antagonist: ligand that binds to  receptor, prevents receptor function• Co...
Nootropic• Mice over-expressed  NMDA2B in the forebrain  were tested on the  object-recognition test.Tang et al. (1999). N...
Central Dogma• DNA    ->    RNA        ->   Protein• Deoxyribonucleic acid• Ribonucleic acid• Protein (or peptide)
Where in the brain?VGLUT2        VGLUT1
Where in the brain?     VGLUT 1         VGLUT2          VGLUT3Light = more
Glutamine                      SynthetaseStahl (2000) p. 388
Tag-Team
Glutamate Receptors• Alpha-amino-3-hydroxy-5-methyl-4-isoxazole  proponic acid (AMPA)• Ionotropic (4 subunits)• Regulates ...
Glutamate Receptors       •     Kainate       •     Ionotropic (4 subunits)       •     Regulates Na+       •     Excitato...
Glutamate Receptors•   N-methyl-D-aspartate•   Ionotropic•   Regulates Ca2+•   Co-Agonist: glutamate & (glycine or D-serin...
If only 2 events:
If all 3!
What happens with over-                            production of NMDA?                                                    ...
Additional Binding Site• Phencyclidine (1-(1-  phenylcyclohexyl)piperidine)• Patented in 1952 as Sernyl by Parke-Davis• Di...
Ketamine• NMDA non-competitive antagonist• Schedule III
Ketamine•   NMDA non-competitive antagonist•   Schedule III•   Veterinary and child anesthetic•   Hallucinogen
Ketamine as an EtOH Therapy?    • Long-term alcoholics received i.v. placebo or      ketamine and rated their subjective  ...
Ketamine as an EtOH Therapy?    • Long-term alcoholics received i.v. placebo or      ketamine and rated their subjective  ...
mGluR1-8• Metabotropic Glutamate Receptor1,2,3,4,5,6,7,8• Work with Ionotropic system for Long-Term  Potentiation• Also im...
Amyotrophic lateral sclerosis (ALS)    • Lou Gehrig’s disease    • Progressive degeneration of neurons    • Cause unknown1...
mGluR1 and Motor Function    • Immunocytochemistry comparing conditions    • Open-field and gait-analysis assessed in wild...
Glutamate & Diet• Infant mice were treated with 0.5-4 mg/g MSG                Female Weight   Vehicle   MSG
How neurons die
How neurons die
How neurons die
Glutamate & Neurotoxicity
GABA•   Gamma aminobutyric acid•   Synthesis•   Release•   Receptors•   Inactivation
GABA Jargon• In vivo: in the intact organism• In vitro: tissue culture• Vesicular GABA Transporter: packages GABA &  glyci...
GABA Jargon• In vivo: in the intact organism• In vitro: tissue culture• Vesicular GABA Transporter: packages GABA &  glyci...
Synthesis
Synthesis
Localization•   Cortex•   Hippocampus•   Cerebellum•   Substantia Nigra
Inactivation• GAT: remove GABA from cleft into neurons or  astrocytes• GABA-T: GABA aminotransferase, breaks down  GABA
GABA Receptors• GABAB: metabotropic• GABAA: ionotropic, channel for Cl-, 5 subunits:  αβγ• Agonists:  – Muscimol (Amanita ...
Neuropharmacology: GABA & Glutamate
Neuropharmacology: GABA & Glutamate
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Neuropharmacology: GABA & Glutamate

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Lecture 7 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University.

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Neuropharmacology: GABA & Glutamate

  1. 1. Glutamate & GABA Brian J. Piper, Ph.D.
  2. 2. Goals• Glutamate – Synthesis – Release – Receptors (NMDA & AMPA, 1-8) – Inactivation• GABA – Synthesis – Release – Receptors (A B C) – Inactivation
  3. 3. Terminology• Glutaminase: enzyme, converts glutamine to glutamate• Glutamine synthetase: enzyme, converts glutamate to glutamine• VGLUT: vesicular glutamate transporter• EAAT: excitatory amino acid transporter for glutamate and aspartate• Astrocytes: type of glia, star shaped
  4. 4. More Terminology• Glutamate: aka glutamic acid• antagonist: ligand that binds to receptor, prevents receptor function• Competitive Antagonist: ligand that binds to a receptor at same location as neurotransmitter• Noncompetitive Antagonist: ligand that binds to a receptor at different location as neurotransmitter
  5. 5. Nootropic• Mice over-expressed NMDA2B in the forebrain were tested on the object-recognition test.Tang et al. (1999). Nature, 401, 63-69.
  6. 6. Central Dogma• DNA -> RNA -> Protein• Deoxyribonucleic acid• Ribonucleic acid• Protein (or peptide)
  7. 7. Where in the brain?VGLUT2 VGLUT1
  8. 8. Where in the brain? VGLUT 1 VGLUT2 VGLUT3Light = more
  9. 9. Glutamine SynthetaseStahl (2000) p. 388
  10. 10. Tag-Team
  11. 11. Glutamate Receptors• Alpha-amino-3-hydroxy-5-methyl-4-isoxazole proponic acid (AMPA)• Ionotropic (4 subunits)• Regulates Na+• Excitatory
  12. 12. Glutamate Receptors • Kainate • Ionotropic (4 subunits) • Regulates Na+ • Excitatory2 min: http://www.youtube.com/watch?NR=1&feature=endscreen&v=zqhcnTDd3h4 Digenea simplex
  13. 13. Glutamate Receptors• N-methyl-D-aspartate• Ionotropic• Regulates Ca2+• Co-Agonist: glutamate & (glycine or D-serine)• Mg2+ is in channel unless recent firing
  14. 14. If only 2 events:
  15. 15. If all 3!
  16. 16. What happens with over- production of NMDA? Joe TsienTang et al. (1999). Nature, 401, 63-69.
  17. 17. Additional Binding Site• Phencyclidine (1-(1- phenylcyclohexyl)piperidine)• Patented in 1952 as Sernyl by Parke-Davis• Dissociative anesthetic• PCP blocks channel
  18. 18. Ketamine• NMDA non-competitive antagonist• Schedule III
  19. 19. Ketamine• NMDA non-competitive antagonist• Schedule III• Veterinary and child anesthetic• Hallucinogen
  20. 20. Ketamine as an EtOH Therapy? • Long-term alcoholics received i.v. placebo or ketamine and rated their subjective experiences • Craving for alcohol was not increasedKrystal, J. H. (1998). Archives of Psychiatry, 55, 354-360.
  21. 21. Ketamine as an EtOH Therapy? • Long-term alcoholics received i.v. placebo or ketamine and rated their subjective experiences • Craving for alcohol was not increasedKrystal, J. H. (1998). Archives of Psychiatry, 55, 354-360.
  22. 22. mGluR1-8• Metabotropic Glutamate Receptor1,2,3,4,5,6,7,8• Work with Ionotropic system for Long-Term Potentiation• Also important for motor function
  23. 23. Amyotrophic lateral sclerosis (ALS) • Lou Gehrig’s disease • Progressive degeneration of neurons • Cause unknown1 min: http://www.youtube.com/watch?v=g0Q4kIx95aU 1903-1941
  24. 24. mGluR1 and Motor Function • Immunocytochemistry comparing conditions • Open-field and gait-analysis assessed in wild type (a), knock-out (c), and restored (e)Ichise et al. (2000). Science, 288, 1832-1835.
  25. 25. Glutamate & Diet• Infant mice were treated with 0.5-4 mg/g MSG Female Weight Vehicle MSG
  26. 26. How neurons die
  27. 27. How neurons die
  28. 28. How neurons die
  29. 29. Glutamate & Neurotoxicity
  30. 30. GABA• Gamma aminobutyric acid• Synthesis• Release• Receptors• Inactivation
  31. 31. GABA Jargon• In vivo: in the intact organism• In vitro: tissue culture• Vesicular GABA Transporter: packages GABA & glycine into vesicles• GAT: takes GABA into astrocytes (1-3) or neurons (1-2)
  32. 32. GABA Jargon• In vivo: in the intact organism• In vitro: tissue culture• Vesicular GABA Transporter: packages GABA & glycine into vesicles• GAT: takes GABA into astrocytes (1-3) or neurons (1-2)• Reversible Enzyme Inhibitor: drug that temporarily binds enzyme• Irreversible Enzyme Inhibitor: drug that permanently binds enzyme
  33. 33. Synthesis
  34. 34. Synthesis
  35. 35. Localization• Cortex• Hippocampus• Cerebellum• Substantia Nigra
  36. 36. Inactivation• GAT: remove GABA from cleft into neurons or astrocytes• GABA-T: GABA aminotransferase, breaks down GABA
  37. 37. GABA Receptors• GABAB: metabotropic• GABAA: ionotropic, channel for Cl-, 5 subunits: αβγ• Agonists: – Muscimol (Amanita muscaria) – Alcohol – Benzodiazepines – Barbiturates• Antagonist: – Picrotoxin

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