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

The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) are gl ucocorticoid-activated transcription factors essential for maintenance of c ellular homeostasis. Differential activation of these adrenocorticosteroid receptors (ACR) is thought to influence neuronal viability, particularly un der challenging cellular conditions. The present study is designed to deter mine the effects of receptor blockade and excitotoxic insult on MR and GR m RNA expression and neuronal viability in hippocampus. Male Sprague-Dawley r ats were pretreated for 48 hr with vehicle, MR antagonist spironolactone (S PIRO) (50 mg/ kg, twice daily, s.c.), or GR antagonist RU486 (25 mg/kg, twi ce daily, s.c.) and subsequently injected with saline or the glutamate anal og 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 hippocampa l neurons were counted to assess KA-induced cell loss. MR blockade with SPI RO increased basal MR mRNA levels in hippocampal subregions CA1, CA3, and d entate gyrus (DG) and increased basal GR mRNA levels in CA3. GR blockade wi th RU486 increased basal GR mRNA levels in CA3. The excitotoxin I(A decreas ed MR mRNA levels in CA1 and CA3, decreased GR mRNA levels in DG, and negat ed all antagonist-induced increases of ACR mRNAs. Cell counts quantifying K A damage indicated increased CA3 vulnerability to KA insult after treatment with MR antagonist spironolactone but demonstrated no significant cell los s in any other group or region. These results demonstrate dynamic regulatio n 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. (C) 2001 Wiley-Liss, Inc.