Dexamethasone (DEX) is a widely used synthetic glucocorticoid whose effects are mediated via glucocorticoid receptor (GRs). Synthetic glucocorticoids are widely used in the clinical setting, due to their potent anti-inflammatory actions. However they are associated with numerous systemic side-effects and may also promote cognitive dysfunction, including impaired memory and learning processes in both patients and animal models.
Discrete pulses of endogenous GR ligands corticosterone (rats) or cortisol (humans) promote pulsatile activation of GR, with GR activity returning to baseline levels during the interpulse interval (within 60 min). In cell lines, prolonged GR activation occurs following a single pulse of DEX. However the duration of DEX-induced GR activation in vivo is unreported. Therefore, we have used Western blotting of GR in purified nuclear extracts obtained from discrete brain regions from adult male SpragueDawley rats following single SC DEX injections. We found DEX promoted significantly prolonged GR activation times compared to endogenous ligand in brain regions associated with memory and learning processes including the hippocampus, amygdala, and perirhinal cortex.
We next assessed the effects of a sub-chronic DEX treatment paradigm, using rats injected twice-daily over 5 days. In situ hybridization histochemistry was used to measure treatment-related changes in mRNA for CRH in the PVN, and GR and MR within the hippocampus. CRH mRNA was significantly downregulated after treatment with 1 mg/kg DEX, but not 500 μg/kg. These findings strongly support chronic central GR activation resulting from the 1 mg/kg treatment. Interestingly, no changes in GR mRNA levels were observed within the hippocampus with either dose, whilst significant upregulation of MR mRNA was measured in the CA2 and CA3 subfields in response to 1 mg/kg DEX.
Since we have shown significantly prolonged GR activation in memory-and-learning dependent regions in vivo following DEX treatment, this is likely to contribute to mechanisms which may underlie DEX-induced cognitive deficits.