Zinc inhibition of gamma-aminobutyric acid(A) receptor function is decreased in the cerebral cortex during pilocarpine-induced status epilepticus.

Functional modulation of gamma-aminobutyric acid(A) (GABA(A)) receptors by Zn(2+), 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, Zn(2+) dose-dependently inhibited muscimol-stimulated uptake of (36)Cl(-) in cortical and cerebellar membranes. However, Zn(2+) inhibition of stimulated (36)Cl(-) 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 Zn(2+) response in the cortex appeared to be selective to Zn(2+) only, because pentobarbital-, alphaxalone-, or flunitrazepam enhancement of muscimol-stimulated (36)Cl(-) uptake did not change in this brain region either at 1 or 2 h after seizures. Because this loss of Zn(2+) 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 Zn(2+) response. We found that, in rats where status epilepticus was terminated by diazepam within 30 min after seizure onset, Zn(2+) response was preserved in the cortex. These findings suggest that continuous seizures of pilocarpine-induced status epilepticus caused a rapid and selective decrease in Zn(2+) 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.