Abstract

Functional modulation of γ-aminobutyric acid_A(GABA_A) receptors by Zn²⁺, pentobarbital, neuroactive steroid alphaxalone, and flunitrazepam was studied in the cerebral cortex and cerebellum of rats undergoing status epilepticus induced by pilocarpine. Under control conditions, Zn²⁺ dose-dependently inhibited muscimol-stimulated uptake of ³⁶Cl⁻ in cortical and cerebellar membranes. However, Zn²⁺ inhibition of stimulated³⁶Cl⁻ uptake was selectively decreased in the cortex (but not in the cerebellum) 1 to 2 h after the onset of status epilepticus. This loss of Zn²⁺ response in the cortex appeared to be selective to Zn²⁺ only, because pentobarbital-, alphaxalone-, or flunitrazepam enhancement of muscimol-stimulated ³⁶Cl⁻ uptake did not change in this brain region either at 1 or 2 h after seizures. Because this loss of Zn²⁺ response in the cortex was apparent only about 1 h after the onset of status epilepticus but not earlier, we tested whether status epilepticus was critical for the development of the loss of Zn²⁺ response. We found that, in rats where status epilepticus was terminated by diazepam within 30 min after seizure onset, Zn²⁺ response was preserved in the cortex. These findings suggest that continuous seizures of pilocarpine-induced status epilepticus caused a rapid and selective decrease in Zn²⁺ inhibition of GABA_A receptor function in the cortex. The possible relevance of such rapid seizure-induced GABA_A receptor plasticity in the cerebral cortex is discussed.