Glutamate • Location • Pharmacology • Physiology – Riluzole: ALS – Synthesis: Glutamine, SNAT, – Memantine: AD Glutaminase – Amantadine: PD

– Storage: VGluT1-3 – Lamotrigine: Seizures, Bipolar, – Release: mGluRII Autoreceptor pain – Receptor – Ketamine: Pain, Depression • Ionotropic: AMPA, Kainate, • Excitotoxicity NMDA – Stroke-induced Brain Damage • Metabotropic: mGluR I, mGluR II, mGluR III • Schizophrenia – Reuptake – PCP: Psychotomimetic Effects • Glia cell: EAAT1/2 – NMDA Receptors • Neuron: EAAT3/4 – mGluRII – Degradation: Glutamine Synthetase

Dr. Shi, Phys I, 2014 1 Glutamate Glutamate Neurons

Dr. Shi, Phys I, 2014 2 Glutamate Glutamate-Glutamine Cycle

Dr. Shi, Phys I, 2014 3 Glutamate Glutamate Receptors

• Ionotropic – AMPA – Kainate – NMDA • Co-Agonist: Glycine

• Metabotropic

– Group I (mGluR1,5, Gs or Gq)

– Group II (mGluR2,3, Gi or Go)

– Group III (mGluR4,6,7,8, Gi or Go)

Dr. Shi, Phys I, 2014 4 Glutamate Clinically Used Glutamate Antagonists

Riluzole Amyotrophic lateral Blocks Na+ channels, decreases glutamate sclerosis release, increases glutamate uptake Memantine Alzheimer's disease Noncompetitive NMDA receptor antagonist

Amantadine Parkinson's disease; Noncompetitive NMDA receptor antagonist Influenza A Lamotrigine Seizures; Bipolar disorder; Inhibits Na+ channels, thereby inhibiting Pain release of excitatory amino acids Ketamine Analgesic, anesthetic, NMDA channel blocker antidepressant, but psychotomimetic

Dr. Shi, Phys I, 2014 5 Glutamate Glutamate in Stroke-Induced Excitotoxicity

Dr. Shi, Phys I, 2014 6 Glutamate Glutamate Hypothesis of Schizophrenia

mGluR II Autoreceptor (-)↓ PCP → ↓NMDA → ↑Glutamate → Psychotic Symptoms

Dr. Shi, Phys I, 2014 7 GABA

• Location • Pharmacology • Physiology – Drugs inhibiting GABA – Synthesis: Glutamate, • Synthesis Glutamic Acid • Release Decarboxylase (GAD) • Uptake • Metabolism – Storage: VGAT – GABA agonists and – Receptor: GABAA, GABAB, antagonists GABA C – GABA modulators – Uptake: GAT1-4 • Benzodiazepines – Metabolism: GABA-T • Barbiturates (GABA-Transaminase)

Dr. Shi, Phys I, 2014 8 GABA GABA Neurons

Dr. Shi, Phys I, 2014 9 GABA Physiology

Dr. Shi, Phys I, 2014 10 GABA GABA Receptors

• GABAA – IPSPs – α1-6, β1-3, γ1-3, δ, ε, π, θ – Synaptic (γ) and extrasynaptic (ε, θ) – Neurosteroids • Alfaxalone

• GABAB – GPCR - Gαi and Gαo –  adenylyl cyclase,  K+ and  Ca2+ channels – Autoreceptors

• GABAC (GABAA-ρ(rho) receptor) – ρ1-3 – Retina

Dr. Shi, Phys I, 2014 11 GABA

Pharmacology

1. GABA Synthesis Allylglycine Inhibits GAD Convulsant

2. GABA Release Tetanus toxin Inhibits GABA and glycine Convulsant release 3. GABA Reuptake Tiagabine Inhibits GAT-1 Anticonvulsant

4. GABA Metabolism Vigabatrin Inhibits GABA-T Anticonvulsant

Dr. Shi, Phys I, 2014 12 GABA

GABA Agonists and Antagonists

GABA Receptor Agonists

Muscimol GABAA receptor agonist Mimics psychosis

Gaboxadol GABAA receptor agonist Anticonvulsant

Baclofen GABAB receptor agonist Muscle relaxant

GABAAReceptor Antagonists

Bicuculline Competitive antagonist Convulsant

Gabazine

Picrotoxin Noncompetitive, channel blocker

Dr. Shi, Phys I, 2014 13 GABA GABA Modulators

• Effect Benzodiazepines 200% – Increase GABA affinity GABA + Barbiturate – Anticonvulsant, anxiolytic 100% – Z-drugs: Zolpidem GABA+BZD GABA • Barbiturates – Increase GABA efficacy 0% [GABA] – Anticonvulsant, anesthetic

Dr. Shi, Phys I, 2014 14