The hypothalamic-pituitary-adrenal (HPA) axis is one of the most widely studied of the stress responsive systems. This cascade begins with the release of CRH from the parvocellular neurons of the paraventricular nucleus of the hypothalamus into the external zone of the median eminence. From here CRH is carried through the portal blood system to the anterior lobe of the pituitary gland, where it acts as a secretagogue for adrenocorticotrophic hormone (ACTH). ACTH is then released into the systemic circulation and carried through the blood to the adrenal cortex, where it stimulates cells in the zona fasciculata to produce and release glucocorticoids. The glucocorticoid released in response to stress in the rat is corticosterone (CORT), while the human adrenal cortex secretes cortisol. Since corticosterone and cortisol vary only slightly in their chemical structure, both are classified as glucocorticoid hormones and bind to the same receptors in the body with comparable affinity. It is perhaps important to note that other species such as hamsters co-secrete corticosterone and cortisol during times of stress. As a result, it is necessary to measure cortisol and corticosterone in species that produce both of these glucocorticoid hormones during times of stress.
Although glucocorticoid secretion is the ultimate hormonal endpoint of the HPA axis, this is just the beginning of the most important physiological effects of HPA activation. Being highly lipophilic, glucocorticoids travel through the blood and passively diffuse across plasma membranes where they bind to cytosolic receptors (Drouin et al., 1992). When activated, the glucocorticoid-receptor complex translocates to the nucleus of the cell and has the ability to alter gene transcription. This in turn leads to glucose mobilization for the organism, alterations in immune function, and changes in CNS functioning [see Munck et al. (1984) for a classic review of glucocorticoid function]. Furthermore, glucocorticoids can bind to receptors in the hippocampus, hypothalamus, and the anterior pituitary and subsequently decrease the release of CRH and ACTH. This serves as a negative feedback mechanism that limits the amount of glucocorticoid secreted in response to subsequent stressors (e.g., Spencer et al., 1998).
As mentioned previously, the effects of CORT are mediated by two high-affinity intracellular receptors. These two receptors are referred to as mineralocorticoid receptors (MR; or type I receptors) and glucocorticoid receptors (GR; or type II receptors). The affinity of MR (Kd = 0.5 to 1 nM) for CORT is greater than that of GR (Kd = 5 to 10 nM), which leads to greater occupancy of MR under basal CORT conditions (Spencer et al., 1993). Both of these receptors are located in the cytoplasm until they become occupied by CORT. Receptor occupation leads to rapid receptor translocation to the nucleus where the receptor acts as a hormone-activated transcription factor (Drouin et al., 1992). Thus, the number of cytoplasmic CORT receptors reflects the number of unoccupied CORT receptors, while the number of nuclear CORT receptors reflects the number of occupied/activated CORT receptors. Indeed, the relative proportion of occupied receptors in the rat given different circulating levels of CORT has been well characterized (Spencer et al., 1993).
The magnitude and temporal dynamics of the CORT response varies markedly with the type and duration of the stressor. However, the time course of increases in plasma CORT levels in response to stress is slightly delayed relative to indices of sympathetic nervous system activity (as discussed in the previous section). For instance, observable increases in CORT can usually be detected within 3 to 5 min from the onset of the stressor, while a maximal CORT response is generally only observed if the stressor persists for at least 20 to 30 min. Finally, the stress-induced rise in CORT typically dissipates completely within 60 to 90 min following termination of the stressor (Jacobson et al., 1988). Thus, the unique temporal dynamics of the pituitary-adrenal response to stress must be taken into serious consideration when designing experiments to examine the potential role of glucocorticoids in mediating the ultimate health consequences of stressor exposure.
Implications for Biological Psychiatry. There are several facets of HPA activation that are particularly relevant for biological psychiatry. First and foremost, prolonged exposure to high circulating levels of CORT (such as with chronic stress) produce deleterious effects on normal CNS function. Since the hippocampus is extraordinarily rich in both MR and GR expression, it is not surprising that the hippocampal system has been the subject of intense scrutiny with regard to glucocorticoid action. Specifically, sustained high levels of CORT have been shown to produce dendritic atrophy (Galea et al., 1997), reduced neurogenesis (Cameron and McKay, 1999), and in extreme cases neurotoxicity (Reagan and McEwen, 1997) within the hippocampus. Such empirical findings have led to the belief that chronic stress throughout the life span—and the prolonged glucocorticoid exposure that ensues—may contribute to the development of multiple psychiatric conditions such as major depression, Cush-ings syndrome, posttraumatic stress disorder (PTSD), and age-related dementia [see Chapter 11 and Sapolsky (2000) for a recent review].
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