Changes in cumulative glucocorticoid exposure may be in itself a factor in the habituation process. The addition of a stress response atop the normal circadian rhythm adds to the “total” level of glucocorticoids seen by the organism, which may modulate ongoing excitability of key regulatory sites and thereby limit responsiveness. Habituation to repeated stress is blocked by pre-stress injections of an MR antagonist (Cole et al., 2000), suggesting that the process may be regulated in part by glucocorticoid signaling via the MR. Unlike variable or “severe” stress regimens [e.g., chronic social stress, chronic unpredictable stress (Chao et al., 1993; Herman et al., 1995)] repeated restraint stress does not down-regulate GR and MR mRNA expression (hippocampus) (Girotti et al., 2006), suggesting that neural feedback mechanisms remain intact. While an elevated feedback signal may be relevant to habituation, it does not constrain the HPA response to new stressors, which can be as great or greater than responses seen in stress-naïve animals (see below) (Akana et al., 1992; Marti et al., 1994).
