It should be emphasized that the “stress habituated” state does not reflect return to normal physiologic status. Habituating regimens (e.g., repeated brief restraint) result in long-term changes in CNS stress circuits, including up-regulation of CRH expression in the PVN, even in the context of reduced corticosterone responses to individual restraint sessions. As noted above, despite habituation to homotypic stressors, novel stressors will induce a disproportionately large HPA axis stress response relative to acutely stressed controls (Figure 3) (Akana et al., 1992; Marti et al., 1994). Increases in CRH gene expression and enhanced HPA axis responding indicate that the underlying sensitivity of the HPA axis is increased, even though the response to the repetitive stimulus is diminished.
