Because of its abundance in the brain, its ability to produce hyperpolarizing inhibition of almost all neurons, its association with
benzodiazepines, and the discovery that many
convulsants inhibited its synthesis,
gamma-aminobutyric acid (
GABA) has often appeared to be the key to
epilepsy. Many assumed that "primary" or "genetic"
epilepsy must be a disorder of
GABA synapses and that
GABA agonists would be universal
anticonvulsants if permeability and
drug metabolism were controlled. The
GABA synthetic gene was a logical "candidate gene" for
epilepsy. However, the
GABA-deficiency theory of
epilepsy is less convincing today.
GABA agonists were found to intensify
seizures in some rodent and human cases. Absence and other
generalized seizures in humans often worsened when treated with
GABA transaminase inhibitors such as
gamma-vinyl-GABA. Surprisingly, the
GABA transaminase inhibitors appear to be more useful in partial than in
generalized epilepsies. Neuronal
GABA uptake blockers are proconvulsant.
GABA agonists aggravate
seizures in several mutants, ranging from the photosensitive baboon to the genetically
epilepsy-prone rat. How can this be understood?
Muscimol injections into the pedunculopontine nucleus increase
seizures due to systematically administered
convulsants, while the receptor blocker
bicuculline suppresses
seizures after injection into several brain regions, including the striatum. The result of inhibiting inhibitory circuits is excitation. Studies with
GABA uptake blockers and the GABAB agonist
baclofen are presented in which their combined administration provoked
seizures in rats.
Baclofen was shown also to increase the incidence of
seizures evoked by
pentylenetetrazole without increasing
seizures due to local
injections of
excitatory amino acids.
Baclofen antagonized the myoclonic effect of
5-hydroxytryptophan in rats with
serotonin lesions.
Baclofen augments some
seizures and inhibits others. Selective inhibition of a particular tract, whether GABAergic or not, may have
convulsant or
anticonvulsant effects, depending on its connections and the state of the organism. GABAA receptor stimulation is usually but not always
anticonvulsant. GABAB receptor stimulation may facilitate absence
seizures and related primary
generalized seizures. GABAB receptors may be abnormal in some forms of nonfocal
epilepsy seen in childhood. It is likely that mutations of
GABA transporter and GABAA receptor genes will be found in humans but they will probably not be patients with "pure
epilepsy."