The Hypothalamus PituitaryAdrenal Axis

Glucocorticoid hormones (cortisol in humans and corticosterone in rodents) are the final step of the activation of the hypothalamic-pituitary-adrenal (HPA) axis, one of the major systems implicated in responding to environmental modifications. Activation of the HPA axis is determined by brain inputs to the hypothalamus, which releases corti-cotropin-releasing hormone (CRH); CRH reaches the hypophysis via the hyphophyseal portal system and activates the release of ACTH in the bloodstream, which, in turn, triggers the secretion of glucocorticoids by the cortical part of the adrenal gland (for review, see ref. 1). The secretion of glucocorticoids is characterized by a circadian cycle. Concentrations of these hormones are low during the inactive phase (dark phase in humans and light phase in rodents) and rise during the first hours that precede the active phase (2). The secretion of glucocorticoids is also activated by practically all forms of stress, which induces a rapid and large increase in hormone levels (for review, see ref. 3). Stress-induced glucocorticoid secretion has been extensively studied and is considered one of the principal adaptive responses to environmental challenges (for review, see ref. 4).

Glucocorticoids have many peripheral effects that principally involve modulation of energy metabolism and of the immune system. These hormones also readily reach the brain, where they exercise a negative feedback on their own secretion and where they regulate many behavioral and neurobiological activities (for review, see ref. 5). These effects are mediated by binding of glucocorticoids to two receptors: the mineralocorti-

From: Molecular Biology of Drug Addiction Edited by: R. Maldonado © Humana Press Inc., Totowa, NJ

coid receptor (MR) and the glucocorticoid receptor (GR) (1,5,6). These receptors are hormone-activated transcription factors belonging to the family of the nuclear receptors. In the inactive state, GRs and MRs are located in the cytoplasm. Upon activation by glucocorticoids, these receptors migrate to the nucleus, where they bind to specific responsive elements located on the promoters of many genes and activate or repress transcription (for review, see ref. 5). In the brain, MRs are principally located in the septo-hippocampal system, whereas GRs have a more widespread distribution. Because of their different affinity for glucocorticoids, MRs are practically saturated by low basal levels of the hormone; in contrast, GRs are only activated during the circadian elevation of the hormones and after stress (5). Consequently, it is generally believed that the effects of stress-induced corticosterone secretion are mediated by GRs.

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