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Pharmacology 18a - Principles of GABAergic Transmission Anil Chopra 1. Which are the principal inhibitory and excitatory amino acid neurotransmitters in the mammalian CNS? With which types of neurons are these transmitters associated? 2. Briefly describe the processes involved in GABAergic synaptic transmission. How may this knowledge be useful in the design of novel therapeutically useful drugs? 3. Compare and contrast the principal characteristics of GABA-A and GABA-B receptors There are a number of different types of neurotransmitter in the CNS: Inhibitory (neutral amino acids) GABA (γ-AMINOBUTYRIC ACID) GLYCINE Excitatory (acidic amino acids) GLUTAMATE ASPARTATE (L-HOMOCYSTEATE?) GABA GABA is mainly found in the central nervous system in the cortex, cerebellum, hippocampus, corpus striatum, and hypothalamus and in the dorsal horn of the spinal cord. GABA neurones are generally short intermediate inhibitory neurones which therefore have a widespread inhibitory action. It has a number of different functions: i) Motor Activity [Cortex, Cerebellum, Cord] GABA SYNTHESIS ii) Extrapyramidal Activity [Basal Ganglia] GABA ‘shunt’ iii) Emotional Behaviour [Limbic System] iv) Endocrine Function [Hypothalamus] GAD GABA Synthesis GABA GAD = Glutamate decarboxylase GABA-T = Gamma-Aminobutyric Acid Transaminase SSDH = Succinic semialdehyde Succinic semialdehyde dehydrogenase Transaminase GABA-T Glycine -Oxoglutarate Succinate SSDH Aspartate Glyoxylate Glutamate KREBS CYCLE Oxaloacetate Transaminase Inhibitory amino acids Excitatory amino acids Oxaloacetate α-oxoglutarate Krebs Cycle Glutamate GABA GABA-T GAD GABA Transaminase GABA Decarboxylase GABA Storage and Release GABA is stored in vesicles in nerve terminals (like any other neurotransmitter) and is released by exocytosis upon influx of calcium ions. GABA Receptors There are 2 types of GABA receptor: GABAA Generally POSTsynaptic When activated by GABA cause influx of Cl- ions This causes the cell to hyperpolarise which will decrease the likelihood of it firing an action potential. Agonised by muscimol (+ GABA) Antagonised by bicuculline (competitive), picrotoxin (non-competitive) and convulsant. GABAB Generally PREsynaptic Inhibit the release of neurotransmitter They are autoreceptors that inhibit GABA release Heterocpetors e.g. reduce dopamine release at dopaminergic synapses. The are G-protein linked and hence use cAMP as a second messenger. They cause a decrease in Ca2+ conductance and an increase in K+ conductance. Agonised by baclofen (often used as muscle relaxant). Oxaloacetate α-oxoglutarate Glutamate GABA Antagonised by phaclofen and saclofen. GABA Inactivation Krebs Cycle GABA-T GAD GABA is taken into the presynaptic neuronal cells as well as into glial cells. This GABA Transaminase GABA Decarboxylase process is Na+ - dependent, energy dependent and saturable. GABA Metabolism GABA is converted into Succinic semialdehyde by GABA Transaminase and then the succinic semialdehyde is converted to succinic acid by succinic semialdehyde dehydrogenase. Succinic Semi-aldehyde GABA Succinic Acid GABA-T SSDH GABA Transaminase Succinate Semialdehyde Dehydrogenase This occurs in the mitochondria of the pre-synaptic neurones and glial cells. Both sodium valproate and vigabatrin inhibit the metabolism of GABA. Krebs Cycle