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.

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 Neuropharmacology: GABA & Glutamate Presentation Transcript

  • Glutamate & GABA Brian J. Piper, Ph.D.
  • Goals• Glutamate – Synthesis – Release – Receptors (NMDA & AMPA, 1-8) – Inactivation• GABA – Synthesis – Release – Receptors (A B C) – Inactivation
  • 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
  • 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
  • Nootropic• Mice over-expressed NMDA2B in the forebrain were tested on the object-recognition test.Tang et al. (1999). Nature, 401, 63-69.
  • 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 Na+• Excitatory
  • Glutamate Receptors • Kainate • Ionotropic (4 subunits) • Regulates Na+ • Excitatory2 min: http://www.youtube.com/watch?NR=1&feature=endscreen&v=zqhcnTDd3h4 Digenea simplex
  • Glutamate Receptors• N-methyl-D-aspartate• Ionotropic• Regulates Ca2+• Co-Agonist: glutamate & (glycine or D-serine)• Mg2+ is in channel unless recent firing
  • If only 2 events:
  • If all 3!
  • What happens with over- production of NMDA? Joe TsienTang et al. (1999). Nature, 401, 63-69.
  • Additional Binding Site• Phencyclidine (1-(1- phenylcyclohexyl)piperidine)• Patented in 1952 as Sernyl by Parke-Davis• Dissociative anesthetic• PCP blocks channel
  • 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 experiences • Craving for alcohol was not increasedKrystal, J. H. (1998). Archives of Psychiatry, 55, 354-360.
  • 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.
  • 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
  • Amyotrophic lateral sclerosis (ALS) • Lou Gehrig’s disease • Progressive degeneration of neurons • Cause unknown1 min: http://www.youtube.com/watch?v=g0Q4kIx95aU 1903-1941
  • 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.
  • 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 & glycine into vesicles• GAT: takes GABA into astrocytes (1-3) or neurons (1-2)
  • 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
  • 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 muscaria) – Alcohol – Benzodiazepines – Barbiturates• Antagonist: – Picrotoxin