Involvement of GABA(A) and GABA(B) receptors in afterdischarge generation in rat hippocampal slices.
It has been hypothesized that a disruption of gamma-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 GABA(A) and GABA(B) receptors on ictal-like afterdischarges (ADs) induced following repetitive high-frequency electrical stimulation in the CA1 region of rat hippocampal slices. The GABA(A) receptor antagonist bicuculline (5 microM) fully blocked AD generation, as did the GABA(A) receptor agonist muscimol (2 microM), which is thought to produce a tonic inhibition during application. However, the benzodiazepine receptor agonist diazepam (5 microM), 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 GABA(B) receptor antagonist phaclofen (1 mM) increased the number of spikes in the AD to 234.7% of the control value, while the GABA(B) receptor agonist baclofen (5 microM) reduced it to 46.9%. We therefore conclude that synaptic, but not tonic, activation of GABA(A) receptors appears to be necessary for ictal-like AD generation, while GABA(B) receptor activation plays a protective role. We therefore propose a modification to the simple disinhibition hypothesis.
Higashima
M
M
Department of Neuropsychiatry, School of Medicine, Kanazawa University, 13-1 Takara-machi, 920-8641, Kanazawa, Japan. mtohma@med.kanazawa-u.ac.jp
Ohno
K
K
Kinoshita
H
H
Koshino
Y
Y
D000818:Animals; D004558:Electric Stimulation; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D018080:Receptors, GABA-B / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D018756:GABA Antagonists; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B