The impact of chronic stress is also evident at the pituitary and adrenal. Chronic stress exposure causes up-regulation of proopiomelanocortin mRNA expression and protein content (Shiomi et al., 1986), consistent with enhanced capacity for release of ACTH. At the adrenal, chronic variable stress causes cellular hypertrophy and hyperplasia in the zona fasciculata of the adrenal cortex, which causes elevated responsiveness to ACTH (Ulrich-Lai et al., 2006). The PVN, pituitary and adrenal changes occur with the context of relatively small changes in resting glucocorticoid secretion, consistent with modulation of the overall capacity of the HPA axis to respond (rather than a pronounced and prolonged basal hypersecretion). The peripheral changes likely reflect the overall cumulative impact (severity) of the stress regimen, as mild or habituating regimens may not be sufficient to cause frank changes at the brain, pituitary, and adrenal level [e.g., attenuated stress-induced adrenal hypertrophy (Flak et al., 2012) and deceased induction of PVN vasopressin mRNA expression (Gray et al., 2010)].
