GABA and epilepsy: basic concepts from preclinical research.

The role of gamma-aminobutyric acid (GABA) transmission in the control of convulsive epileptic seizures is considered from the perspective of the actions of drugs that augment GABA transmission in the brain. In particular, the effects of a directly acting GABAA receptor agonist, muscimol, is compared with the effects of a GABA-elevating agent, gamma-vinyl GABA (GVG, vigabatrin), in animal models of convulsive seizures. Evidence indicates that there are certain regions of the brain where enhanced GABA transmission is anticonvulsant; in other regions, blockade of GABA transmission exerts anticonvulsant actions. In addition, there are brain areas in which the effects of muscimol and GVG are distinct from one another, owing to a relatively low level of endogenous GABA transmission in those areas. The direct stimulation of postsynaptic GABA receptors (by direct receptor agonists) bypasses normal mechanisms of synaptic transmission and can evoke abnormal neurological symptoms, whereas the enhancement of presynaptic availability of GABA avoids these complications. GVG acts to boost presynaptic GABA stores, which can then be utilized physiologically; this may account for the relatively low incidence of CNS-related side effects with anticonvulsant doses of GVG. It is suggested that greater attention be focused on ways of enhancing endogenous GABA availability in future drug development for the control of seizure disorders.