neuropharmacology: gaba & glutamate
DESCRIPTION
Lecture 7 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. ([email protected]) at Willamette University.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 VGLUT3
Light = more
GlutamineSynthetase
Stahl (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+
• Excitatory
Digenea simplex2 min: http://www.youtube.com/watch?NR=1&feature=endscreen&v=zqhcnTDd3h4
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?
Tang et al. (1999). Nature, 401, 63-69.
Joe Tsien
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 increased
Krystal, 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 increased
Krystal, 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 unknown
1 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: α β γ
• Agonists: – Muscimol (Amanita muscaria)– Alcohol– Benzodiazepines– Barbiturates
• Antagonist:– Picrotoxin