Involvement of GABAA and GABAB receptors in afterdischarge generation in rat hippocampal slices

It has been hypothesized that a disruption of γ-aminobutyric acid (GABA) receptor-mediated processes may be involved in the pathophysiology of focal epilepsy. This disinhibition hypothesis has been postulated from the results of in vitro experiments of the interictal activity of focal epilepsy. Less is known, however, about how disinhibition may be involved in the production of the ictal activity. We therefore examined the pharmacological effects of selective agonists and antagonists of GABAA and GABAB receptors on ictal-like afterdischarges (ADs) induced following repetitive high-frequency electrical stimulation in the CA1 region of rat hippocampal slices. The GABAA receptor antagonist bicuculline (5 μM) fully blocked AD generation, as did the GABAA receptor agonist muscimol (2 μM), which is thought to produce a tonic inhibition during application. However, the benzodiazepine receptor agonist diazepam (5 μM), which enhances the inhibitory postsynaptic potential induced by synaptically released GABA, increased the number of spikes in the AD to 148.3% of the control value. On the other hand, the GABAB receptor antagonist phaclofen (1 mM) increased the number of spikes in the AD to 234.7% of the control value, while the GABAB receptor agonist baclofen (5 μM) reduced it to 46.9%. We therefore conclude that synaptic, but not tonic, activation of GABAA receptors appears to be necessary for ictal-like AD generation, while GABAB receptor activation plays a protective role. We therefore propose a modification to the simple disinhibition hypothesis.