**3. Glucocorticoids and stress: the** *allostasis* **concept**

During alarm reaction, catecholamines stimulate hypothalamus, which releases hormones to guarantee adequate plasma glucose levels. These hormones become maximal 4 hours after alarm [16, 21]. Thus, glucocorticoids also help in the alarm reaction. Nowadays, stress response is accepted to be undoubtedly associated with *allostasis*, a term created by Sterling and Eyer [30] that textually means *maintaining stability through change*, in the idea that stress situation is a body adaptation to a unknown situation that must be transitory blocked or arrested. System failure would imply suppression of several anabolic processes with energy store diminution and immune system blocking, which can be highly deleterious to the body.

When stress becomes chronic, a high glucocorticoids release to plasma is kept. These high levels downregulate the GR expression in hippocampus. Thus, the correct feedback exerted by the hypophysis-pituitary axis (HPA) blocking is shunned, which results in lasting high glucocorticoids concentrations [26, 30, 31]. There exist three known mechanisms regulating the entrance of glucocorticoids to the brain [16]: (1) CBG, a molecule that determines the free cortisol levels in humans, and thus cortisol which is available to bind GR [16]. In response to very high free cortisol levels, the CBG transport capacity is saturated and the cortisol levels increased substantially. Thus, the situation is compatible with cortisol resistance or low response to cortisol [32]; (2) glycoprotein P carriers of blood–brain barrier limit, despite glucocorticoid fat solubility, the entrance of cortisol to the brain; and (3) isoenzymes (dehydrogenases or reductases) transform cortisone in active cortisol, which is available to bind GR. Conversely, the 11 β-hydroxysteroid dehydrogenase 2 (11 β-HSD 2) transforms in the kidneys cortisol into inactive cortisone (**Figure 1**). The presence of high renal levels avoid corticoids from interacting on MR. This enzyme is also available at high levels during development in the brain and placenta to protect the body against deleterious effects of high cortisol levels (e.g. cerebellar malformation [33], high HPA activity in adult life [34] and increased incidence of diseases related to corticoids hypersensitivity [22].
