Hippocampal hyperexcitability induced by GABA withdrawal is due to down-regulation of GABA A receptors

The sudden interruption of an intracortical instillation of exogenous γ-aminobutyric acid (GABA) generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal (GW) last for weeks. A similar withdrawal-induced hyperexcitability is also produced by several GABA A receptor agonists. Thi...

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Bibliographic Details
Published in:Epilepsy research 2001-12, Vol.47 (3), p.257-271
Main Authors: Casasola, C, Bargas, J, Arias-Montaño, J.-A, Calixto, E, Montiel, T, Galarraga, E, Brailowsky, S
Format: Article
Language:English
Subjects:
Animals
Benzodiazepine withdrawal
Bicuculline - pharmacology
Down-Regulation
Epilepsy
GABA
GABA A receptors
GABA withdrawal syndrome
gamma-Aminobutyric Acid - pharmacology
Hippocampus
Hippocampus - drug effects
Hippocampus - physiology
In Vitro Techniques
Kinetics
Male
Muscimol - pharmacology
Rats
Rats, Wistar
Receptors, GABA-A - drug effects
Receptors, GABA-A - physiology
Substance Withdrawal Syndrome
Withdrawal syndromes
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Summary:The sudden interruption of an intracortical instillation of exogenous γ-aminobutyric acid (GABA) generates an epileptic focus in mammals. Seizures elicited by GABA withdrawal (GW) last for weeks. A similar withdrawal-induced hyperexcitability is also produced by several GABA A receptor agonists. This work reports a quantitative analysis of GW-induced hyperexcitability produced in the hippocampus in vitro. GW produced a left-ward displacement of the input/output (I/O) function, suggesting that the postsynaptic component is predominant to explain the hyperexcitability. A decrease in the inhibitory efficacy of the GABA A receptor agonist, muscimol, confirmed that inhibition was impaired. Binding saturation experiments demonstrated a decrease in [ 3H]-muscimol binding after GABA withdrawal showing a close correlation with the development of hyperexcitability. All these modifications coursed without changes in receptor affinity ( K D) for muscimol or bicuculline as demonstrated by both binding studies and Schild analysis. It is concluded that, in the CA1 region of the hippocampus, it is the number of functional GABA A receptors, and not the affinity of the receptor, what is decreased during GW-induced hyperexcitability.
ISSN:0920-1211
1872-6844
DOI:10.1016/S0920-1211(01)00314-X