Adrenocorticosteroid receptor blockade and excitotoxic challenge regulate adrenocorticosteroid receptor mRNA levels in hippocampus.

Abstract

The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) are glucocorticoid-activated transcription factors essential for maintenance of cellular homeostasis. Differential activation of these adrenocorticosteroid receptors (ACR) is thought to influence neuronal viability, particularly under challenging cellular conditions. The present study is designed to determine the effects of receptor blockade and excitotoxic insult on MR and GR mRNA expression and neuronal viability in hippocampus. Male Sprague--Dawley rats were pretreated for 48 hr with vehicle, MR antagonist spironolactone (SPIRO) (50 mg/kg, twice daily, s.c.), or GR antagonist RU486 (25 mg/kg, twice daily, s.c.) and subsequently injected with saline or the glutamate analog kainic acid (KA) (12 mg/kg i.p.). Twenty-four hr post-insult, MR and GR mRNA levels were assessed by in situ hybridization analysis, and hippocampal neurons were counted to assess KA-induced cell loss. MR blockade with SPIRO increased basal MR mRNA levels in hippocampal subregions CA1, CA3, and dentate gyrus (DG) and increased basal GR mRNA levels in CA3. GR blockade with RU486 increased basal GR mRNA levels in CA3. The excitotoxin KA decreased MR mRNA levels in CA1 and CA3, decreased GR mRNA levels in DG, and negated all antagonist-induced increases of ACR mRNAs. Cell counts quantifying KA damage indicated increased CA3 vulnerability to KA insult after treatment with MR antagonist spironolactone but demonstrated no significant cell loss in any other group or region. These results demonstrate dynamic regulation of hippocampal MR and GR mRNAs after ACR antagonist treatment and kainate toxicity, underscoring the potential importance of MR and GR availability to neuronal viability after insult.