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.
Banerjee
P K
PK
Department of Pharmacology, the Brain Research Institute, University of California, Los Angeles, California, USA.
Olsen
R W
RW
Snead
O C
OC
D000818:Animals; D001692:Biological Transport; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D018755:GABA Agonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009118:Muscimol / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology*
D002712:Chlorides; D018755:GABA Agonists; D058787:GABA-A Receptor Antagonists; D018721:Muscarinic Agonists; D011963:Receptors, GABA-A; D010862:Pilocarpine; D009118:Muscimol; D015032:Zinc