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 (-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
GABA shunt
Ganglia]
iii) Emotional Behaviour [Limbic GAD System]
iv) Endocrine Function [Hypothalamus]
Glyoxylate
GABA Glutamate
GABA Synthesis
GAD = Glutamate decarboxylase GABA-T Transaminase
GABA-T = Gamma-Aminobutyric Acid Succinic
Transaminase semialdehyde -Oxoglutarate Glycine

SSDH = Succinic semialdehyde

dehydrogenase SSDH KREBS CYCLE
Succinate

Aspartate Oxaloacetate

Transaminase

Inhibitory amino acids

Excitatory amino acids
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).
Antagonised by phaclofen and saclofen.

GABA Inactivation
GABA is taken into the presynaptic neuronal cells as well as into glial cells. This
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.

This occurs in the mitochondria of the pre-synaptic neurones and glial cells.

Both sodium valproate and vigabatrin inhibit the metabolism of GABA.