GABA and Epilepsy: Their Complex Relationship and the Evolution of Our Understanding

Abstract

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."

Pharmacological modulation of GABAB receptors affects cocaine-induced seizures in mice

“…Consistent with these findings, (€)-baclofen was confirmed to be ineffective against seizures induced by pentylenetetrazole, aminophylline and NMDA in the present study. Further, baclofen potentiated seizures induced by bicuculline and pentylenetetrazole (Snodgrass 1992;Snead 1996;Matejovska et al 1998), and potentiated lethality induced by NMDA (Czuczwar et al 1985a). Likewise, baclofen appeared to potentiate tonic seizures and lethality induced by pentylenetetrazole in the present study.…”

“…A role of GABA B receptors in seizure disorders appears to be more complex as agonists and antagonists of the receptor can produce both anticonvulsant and convulsant effects depending on the type of convulsant stimulus. For example, the prototypical GABA B agonist (€)-baclofen has been reported to induce seizures per se after intraventricular injections in rodents and after therapeutic doses in humans (Rush and Gibberd 1990;Snodgrass 1992). Further, (€)-baclofen potentiated the convulsant effects of acutely administered pentylenetetrazole but attenuated the development of pentylenetetrazole-kindled seizures in rodents (Snodgrass 1992;Snead 1996;De Sarro et al 2000).…”

“…A plethora of evidence has accumulated to document a principal role of g-aminobutyric acid (GABA)-mediated neurotransmission in the neuropathology of seizures in humans and experimental animals (Snodgrass 1992;Bradford 1995). Accordingly, the anticonvulsant effects of many antiepileptic drugs are attributed to their ability to augment GABA A -mediated inhibition (Rogawski and Porter 1990).…”

“…For example, the prototypical GABA B agonist (€)-baclofen has been reported to induce seizures per se after intraventricular injections in rodents and after therapeutic doses in humans (Rush and Gibberd 1990;Snodgrass 1992). Further, (€)-baclofen potentiated the convulsant effects of acutely administered pentylenetetrazole but attenuated the development of pentylenetetrazole-kindled seizures in rodents (Snodgrass 1992;Snead 1996;De Sarro et al 2000). Like baclofen, antagonists of GABA B receptors have demonstrated both anticonvulsant and pro-convulsant effects in different experimental models (Hosford et al 1995;Snead 1996;Vergnes et al 1997;De Sarro et al 2000).…”

5-HT2C and GABAB receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice

“…GABA B receptors have been implicated in a variety of CNS hyperexcitability states (Schuler et al, 2001;Brown et al, 2003;Gassmann et al, 2004;Merlo et al, 2007). Baclofen is proconvulsant for some types of seizures, including models of generalized absence seizures (Marescaux et al, 1992;Snodgrass, 1992), and anticonvulsant in other seizure models (Amabeoku and Chickuni, 1992), suggesting that different brain regions and/or cellular mechanisms influence different seizure types (Carai et al, 2002). Furthermore, in an active neuronal network the net effect of GABA B receptor activation on neuronal excitability is extremely complex due to the dynamic spatial and temporal complexities of synaptic activity within integrated inhibitory and excitatory circuits.…”