Chronic blockade of N-methyl-D-aspartate receptors alters gamma-aminobutyric acid type A receptor peptide expression and function in the rat

Chronic in vivo or in vitro application of GABA(A) receptor agonists alters GABA(A) receptor peptide expression and function. Furthermore, chronic in vitro application of N-methyl-D-aspartate (NMDA) agonists and antagonists a lters GABA(A) receptor function and mRNA expression. However, it is unknown if chronic in vivo blockade of NMDA receptors alters GABA(A) receptor func tion and peptide expression in brain. Male Sprague-Dawley rats were chronic ally administered the noncompetitive NMDA receptor antagonist MK-801 (0.40 mg/kg, twice daily) for 14 days. Chronic blockade of NMDA receptors signifi cantly increased hippocampal GABA(A) receptor alpha(4) and gamma(2) subunit expression while significantly decreasing hippocampal GABA(A) receptor alp ha(2) and beta(2/3) subunit expression. Hippocampal GABA(A) receptor alpha( 1) subunit peptide expression was not altered. In contrast, no significant alterations in GABA(A) receptor subunit expression were found in cerebral c ortex. Chronic MK-801 administration also significantly decreased GABA(A) r eceptor-mediated hippocampal Cl- uptake, whereas no change was found in GAB A(A) receptor-mediated cerebral cortical Cl- uptake. Finally, chronic MK-80 1 administration did not alter NMDA receptor NR1, NR2A, or NR2B subunit pep tide expression in either the cerebral cortex or the hippocampus. These dat a demonstrate heterogeneous regulation of GABA(A) receptors by glutamatergi c activity in rat hippocampus but not cerebral cortex, suggesting a new mec hanism of GABA(A) receptor regulation in brain.