g-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system (CNS) and is widely distributed throughout the brain. Approximately 60-75% of all synapses in the CNS are GABAergic.¹

GABA binds to three principal receptors, each of which is involved in different physiologic functions:

• GABA-A receptors mediate fast inhibitory synaptic transmissions; they regulate neuronal excitability (eg, seizure threshold) and rapid changes in mood; they are targets of benzodiazepines, barbiturates, and ethanol^2,3
• GABA-B receptors mediate slow inhibitory potentials; they appear to be important in memory, mood, and pain⁴
• GABA-C receptors –– their physiologic role has not yet been fully described

GABAergic activity may be enhanced by either:

• Stimulating GABA-A receptors (GABA-A-receptor agonists or modulating compounds)
• Inhibition of GABA metabolism
• Direct inhibition of GABA reuptake from the synapse by blocking the action of GATs (selective GABA-reuptake inhibitors)

GATs are membrane-transporter proteins that remove GABA from the synaptic cleft.

Four distinct GATs have been identified: GAT-1, GAT-2, GAT-3, and BGT-1; they are located on neurons, both pre- and postsynaptically, and on glial cells.⁵ They differ in CNS distribution and localization.

• GAT-1 is the primary GABA transporter in the brain.^3,4
• The density of GAT-1 is highest in the frontal and parietal cortex.