Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: Relevance to post-traumatic stress disorder

Hippocampal glucocorticoid receptors (GR and MR) play an important role in glucocorticoid negative feedback. Abnormalities in negative feedback are fo und in depression and in posttraumatic stress disorder (PTSD), suggesting t hat GR and MR might he involved in the pathophysiology of these disorders. Enhanced negative feedback, the PTSD-specific neuroendocrine abnormality, c an be induced in animals using a single prolonged stress (SPS) paradigm (a number of different stressors in one prolonged session, 'no stress' interva l and a testing session one week later). In the current study, we examined hippocampal GR and MR mRNA distribution in the same animals that exhibited altered negative feedback following the SPS. Seven groups of adult Sprague- Dawley male rats (seven animals each) were used in two studies, comparing u nstressed controls to acutely stressed animals (SPS: 24 h group), SPS anima ls (seven and 14 days), and SPS + chronic stress animals. GR and MR mRNA di stribution across hippocampal subfields was studied using insitu hybridizat ion with S-35-labelled cRNA probes, Acute stress produced down-regulation o f GR and MR mRNA across all hippocampal subfields. Seven days later (SPS-7 group), there was a differential recovery, with GR mRNA reaching higher tha n the prestress levels, and MR mRNA remaining downregulated. The same diffe rential regulation was present in the 14-day group. chronically stressed an imals that exhibited normal fast feedback also had normalization in their G R and MR mRNA levels. The MR/GR ratio was decreased only in animals that ha d enhanced fast feedback. These findings suggest that the increase in GR, i n hippocampus is involved in the fast feedback hypersensitivity observed in the SPS animals, and might also underlie enhanced dexamethasone sensitivit y found in PTSD. Since differential activation of GR and MR can modulate me mory, behavioural responsivity, anxiety and fear, change in MR/GR ratio mig ht also explain other PTSD-related phenomena.