Neuropharmacology: GABA & Glutamate

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