CNS Drug Reviews

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain (24,32,40). It has been well documented that the reduction of GABAergic neuronal activity plays an important role in a number of neurological disorders, including epilepsy, anxiety, and pain (17). GABA is synthesized in nerve endings by the transamination of α-ketoglutaraldehyde to glutamic acid, which is decarboxylated by glutamic acid decarboxylase (GAD) to GABA. GABA release from neurons is of two types (reviewed in refs. 7 and 36). Classical presynaptic release of GABA is vesicular. It occurs through a calcium-dependent mechanism and can be blocked by tetanus toxin. When a propagating wave of depolarization reaches the presynaptic neuronal terminal, voltage-dependent calcium channels are opened and the influx of Ca2+ results in release of neurotransmitter into the synaptic cleft. This calcium-dependent GABA release is regulated by autoreceptors. There is also nonvesicular, calcium-independent GABA release that is secondary to depolarization of the postsynaptic membrane and Na+ influx. This release depends on the reverse of function of the GABA transporter, and it is blocked by GABA-uptake inhibitors such as nipecotic acid (3,30). Glutamate and anoxic depolarization cause release of GABA by this mechanism. Once released GABA diffuses across the synaptic cleft and binds to specific receptors. The effects of GABA are mediated via two distinct classes of receptors. The first of them (the GABAA receptor-coupled chloride ion channel complex) belongs to the ligand-gated channel family. Activation of the GABAA receptor complex by GABA leads to an increased influx of Cl ions, resulting in membrane hyperpolarization and neuronal inhibition. GABAA receptors are located post-synaptically on dendrites, the somatic mem-