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.

1. Glutamate & GABA
Brian J. Piper, Ph.D.

2. Goals
• Glutamate
– Synthesis
– Release
– Receptors (NMDA & AMPA, 1-8)
– Inactivation
• GABA
– Synthesis
– Release
– Receptors (A B C)
– Inactivation

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. 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. Nootropic
• Mice over-expressed
NMDA2B in the forebrain
were tested on the
object-recognition test.
Tang et al. (1999). Nature, 401, 63-69.

6. Central Dogma
• DNA -> RNA -> Protein
• Deoxyribonucleic acid
• Ribonucleic acid
• Protein (or peptide)

7. Where in the brain?
VGLUT2 VGLUT1

8. Where in the brain?
VGLUT 1 VGLUT2 VGLUT3
Light = more

9. Glutamine
Synthetase
Stahl (2000) p. 388

11. Tag-Team

12. Glutamate Receptors
• Alpha-amino-3-hydroxy-5-methyl-4-isoxazole
proponic acid (AMPA)
• Ionotropic (4 subunits)
• Regulates Na+
• Excitatory

13. Glutamate Receptors
• Kainate
• Ionotropic (4 subunits)
• Regulates Na+
• Excitatory
2 min: http://www.youtube.com/watch?NR=1&feature=endscreen&v=zqhcnTDd3h4 Digenea simplex

14. Glutamate Receptors
• N-methyl-D-aspartate
• Ionotropic
• Regulates Ca2+
• Co-Agonist: glutamate & (glycine or D-serine)
• Mg2+ is in channel unless recent firing

15. If only 2 events:

16. If all 3!

17. What happens with over-
production of NMDA?
Joe Tsien
Tang et al. (1999). Nature, 401, 63-69.

18. Additional Binding Site
• Phencyclidine (1-(1-
phenylcyclohexyl)piperidine)
• Patented in 1952 as Sernyl by Parke-Davis
• Dissociative anesthetic
• PCP blocks channel

19. Ketamine
• NMDA non-competitive antagonist
• Schedule III

20. Ketamine
• NMDA non-competitive antagonist
• Schedule III
• Veterinary and child anesthetic
• Hallucinogen

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 increased
Krystal, J. H. (1998). Archives of Psychiatry, 55, 354-360.

22. Ketamine as an EtOH Therapy?
• Long-term alcoholics received i.v. placebo or
ketamine and rated their subjective
experiences
• Craving for alcohol was not increased
Krystal, J. H. (1998). Archives of Psychiatry, 55, 354-360.

23. 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

24. Amyotrophic lateral sclerosis (ALS)
• Lou Gehrig’s disease
• Progressive degeneration of neurons
• Cause unknown
1 min: http://www.youtube.com/watch?v=g0Q4kIx95aU 1903-1941

25. 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.

26. Glutamate & Diet
• Infant mice were treated with 0.5-4 mg/g MSG
Female Weight Vehicle MSG

27. How neurons die

28. How neurons die

29. How neurons die

30. Glutamate & Neurotoxicity

31. GABA
• Gamma aminobutyric acid
• Synthesis
• Release
• Receptors
• Inactivation

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)

33. 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

34. Synthesis

35. Synthesis

36. Localization
• Cortex
• Hippocampus
• Cerebellum
• Substantia Nigra

37. Inactivation
• GAT: remove GABA from cleft into neurons or
astrocytes
• GABA-T: GABA aminotransferase, breaks down
GABA

39. GABA Receptors
• GABAB: metabotropic
• GABAA: ionotropic, channel for Cl-, 5 subunits:
αβγ
• Agonists:
– Muscimol (Amanita muscaria)
– Alcohol
– Benzodiazepines
– Barbiturates
• Antagonist:
– Picrotoxin