The right arm of the inverted U-shaped curve is likely due to potential catabolic effects of glucocorticoids on physiological and cellular functions, most likely mediated by the GR. In keeping with their role in energy redistribution, glucocorticoids promote energy mobilization, including glycogenolysis, lipolysis, and proteolysis (Munck et al., 1984). Thus, these hormones promote processes that, while good for the organism in moderation, can cause long-term cellular energy depletion at high levels. In addition to effects on catabolism, glucocorticoids also inhibit processes related to growth and reproduction (Munck et al., 1984) (the organism does not need to be concerned about growing if energy reserves are being depleted). In brain, high levels of glucocorticoids can inhibit glial glucose transport (Virgin et al., 1991) and impair neuronal survival under conditions of energetic challenge (Tombaugh et al., 1992). Glucocorticoids can also inhibit expression of key neurotrophic molecules, such as brain-derived neurotrophic factor (Smith et al., 1995; Schaaf et al., 2000), and impair hippocampal neurogenesis (Gould and Tanapat, 1999). Finally, glucocorticoids down-regulate GR expression in limbic regions controlling negative feedback (e.g., hippocampus, prefrontal c) (Mizoguchi et al., 2003; Chiba et al., 2012), which limits the ability of the system to control glucocorticoid homeostasis.
