To be clear, glucocorticoid responses are required for survival and adaptation. The relationship between glucocorticoid secretion and adaptation (e.g., in terms of appropriate behavioral performance) is often described as an “inverted-U” shaped curve, wherein an optimal level of glucocorticoid signaling is required to produce the most effective organismal response (De Kloet et al., 1998) (Figure 1). Thus, both hypo- and hyper-secretion generate poor responses, whereas an intermediate level of corticosteroids fosters superior performance. Work from De Kloet and colleagues suggests that the molecular basis of this curious phenomenon lies in the differing binding affinities and signaling characteristics of the two primary corticosteroid receptors in brain (De Kloet et al., 1998). The mineralocorticoid receptor (MR) binds low levels of glucocorticoids, and fosters cellular activation (hippocampus) and maintains basal circadian corticosteroid rhythms. The glucocorticoid receptor (GR) binds glucocorticoids across the circadian peak/stress range, and appears to inhibit hippocampal neurons and controls the magnitude of HPA axis responses to stress via negative feedback mechanisms (Reul and Dekloet, 1985; De Kloet et al., 1998). While MR and GR share virtually identical DNA binding domains,
