The hypothalamicpituitary adrenal axis

Glucocorticoids hormones are the last step of the activation of the HPA axis. Afferent inputs to the hypothalamus induce the release of corticotropin-releasing factor (CRF); CRF reaches the pituitary via the hyphophyseal portal system and activates the release of ACTH in the bloodstream, which, in turn, triggers the secretion of glucocorticoids (Cortisol in humans and corticosterone in rodents) by the cortical part of the adrenal gland (for review, see McEwen et al., 1986). In humans, as in animals, the secretion

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of glucocorticoids is characterized by a circadian cycle whereby glucocorticoid concentrations are low during the inactive phase (dark phase in humans and light phase in rodents) and rise progressively during the hours that precede the active phase, to reach a peak during the first hours of this phase (Akana et al., 1986). Glucocorticoids secretion is also triggered by practically all forms of stresses (for review, see Dallman et al., 1989), and this increase in glucocorticoid levels is considered one of the principal adaptive responses to environmental challenges (for review, see Munck et al., 1984).

Glucocorticoids exert their effects via two types of intracellular corticosteroid receptors: Type I or mineralocorticoid receptors (MRs) and type II or glucocorticoid receptors (GRs). Both MRs and GRs are hormone-activated transcription factors belonging to the family of the nuclear receptors. Upon activation by glucocorticoids, these receptors form homo- or hetero-dimers. In the nucleus, they bind to specific responsive elements located on the promoters of many genes thereby activating or repressing gene transcription (for review, see Joels and de Kloet, 1994). In rodents, brain MRs are mostly located in the septo-hippocampal system, whereas GRs have a more widespread distribution. In addition, MRs have high affinity for corticosterone; because of this, they are saturated by low basal levels of the hormone. On the other hand, GRs have low affinity for the hormone and are activated by high corticosterone levels, such as those observed during the circadian peak, or after stress (Joels and de Kloet, 1994).

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