Glucocorticoids and Behavioral States Reciprocal Determinism

Beta Switch Program

Beta Switch Program by Sue Heintze

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Glucocorticoids (Cortisol in humans, corticos-terone in rats) are steroid hormones of the adrenal cortex that have potent effects on glucose metabolism and immune function, as well as on psychological processes (Gore & Roberts, 2003; Lovallo & Thomas, 2000; Schimmer & Parker, 1996). Glucocorticoids are classic stress hormones and have been commonly used as biochemical markers of stress reactions (McEwen, 2000). As illustrated in Figure 12.6, the secretion of glucocorticoids is regulated by the anterior pituitary hormone adrenocorticotropic hormone (ACTH), which in turn is controlled by the hypothalamic peptide corticotropin releasing hormone (CRH). CRH is released in a pulsatile fashion (see Veldhuis et al., 2001), regulated by pituitary, hypothalamic, and hip-pocampal circuits that bear glucocorticoid receptors and are sensitive to glucocorticoid levels. These circuits exert a feedback inhibitory influence on CRH release. The hypothalamic and pituitary negative feedback mechanisms represent the traditionally recognized routes responsible for short-term regulation of glucocorticoid secretion, whereas the hippocampus appears to be involved in stress reactions and longer term glucocorticoid regulation.

In addition to the short-term pulsatile patterns of release, the hypothalamic-pituitary-adrenal-corti-cal axis (HPAC) displays a circadian rhythm, with plasma glucocorticoid levels peaking in the early morning hours and showing a nadir in the late afternoon and minor peaks around mealtimes (see Lovallo & Thomas, 2000). Glucocorticoids bind to both glucocorticoid (GR) and mineralocorticoid (MR) receptors, and the steroid/receptor complex is translocated to the nucleus, where it can serve as a transcription factor to regulate gene expression (Gore & Roberts, 2003). More rapid actions may be exerted by glucocorticoid binding to membrane bound receptors (see Lupien & McEwen, 1997).

Measurement issues: reliability and validity. The pulsatile nature of ACTH and Cortisol release poses a problem of reliability, as the level of hormone in plasma will vary depending on the time relation of the sampling to the pulsatile pattern of release. One approach to improving reliability has been to take multiple samples (e.g., Veldhuis et al., 2001) and then aggregating over samples if the interest is in tonic levels or preserve the temporal samples if the interest is in time-varying patterns of secretion. An additional measurement complication is the notable circadian rhythm in Cortisol release. The measurement of the diurnal rhythm, by repeated Cortisol measurements across the day, has been used to assess the status of the HPAC. If a more limited sample of Cortisol is desired (e.g., as a stress marker), the diurnal rhythm not only imposes the restriction that samples be taken at the same time of the day, but also raises a question concerning the optimal time for sampling.

Measures derived late in the day or at night generally are not optimal for studies of chronic stress, because of the low levels of secretion and sensitivity limits. Consequently, for measures of chronic stress, samples are commonly taken during peak levels in the morning. The change in Cortisol over 30 minutes (or so) from waking, for example, has been suggested to be a sensitive measure of adreno-

H PAC System and Hormonal Secretion

Circadian Pattern

Circadian Pattern

Figure 12.6. Structures and secretions of the glucocorticoid1 system. Hormones are listed in oval text boxes, and the rectangular inserts illustrate time-varying patterns of secretion or local concentrations, from pulsatile to more steady state, and over the circadian cycle. Solid arrows illustrate sample methods, salivary, vascular, and urinary. As illustrated, plasma Cortisol levels are the highest and most variable and include both bound and unbound hormones, whereas salivary and urinary are more time stable and are considerably lower, as they represent unbound hormones.

Figure 12.6. Structures and secretions of the glucocorticoid1 system. Hormones are listed in oval text boxes, and the rectangular inserts illustrate time-varying patterns of secretion or local concentrations, from pulsatile to more steady state, and over the circadian cycle. Solid arrows illustrate sample methods, salivary, vascular, and urinary. As illustrated, plasma Cortisol levels are the highest and most variable and include both bound and unbound hormones, whereas salivary and urinary are more time stable and are considerably lower, as they represent unbound hormones.

cortical reactivity (Schmidt-Reinwald et al., 1999). Conversely, phasic reactivity to stress may be more appropriately assessed in the afternoon, when basal levels are lower and more stable. Some conditions such as chronic stress or depression may be associated with blunted negative feedback regulation and hence a diminished circadian pattern. This pattern may be more readily identified by evening measures or by indices of circadian fluctuations. Circadian fluctuations are often thought to arise in large part from changes in feedback regulation, but other factors could also impact these rhythms, including altered or disrupted sleep/waking cycles, and should be considered when interpreting differences in circadian fluctuations (Spath-Schwalbe et al., 1993).

A more direct test of feedback control, having high construct validity, is the dexamethasone-sup-pression test. This procedure entails the administration of a standardized dose of the synthetic steroid dexamethasone, along with pre- and postadministration measurements of ACTH or Cortisol. Secretion of these endogenous hormones will be suppressed in proportion to the potency of steroid feedback inhibition. A subset of depressed patients (50%-60%) show elevated Cortisol levels, an attenuated circadian rhythm, and a blunted response to dexamethasone (see Parker, Schatzberg, & Lyons, 2003). This may reflect conditions within brain feedback circuits or changes in glucocorticoid receptor sensitivity. We will return to these possibilities later, in the context of stress effects.

Additional measurement issues arise over the fact that typically less than 10% of plasma Cortisol is in a free, unbound, biologically active state. The rest is reversibly bound to plasma proteins (corti-costeroid-binding globulin, CBG), which decrease bioavailability and metabolic clearance (Breuner & Orchinik, 2002). Adding further complexity is the fact that the proportion of bound Cortisol may vary with Cortisol levels or other physiological conditions, Moreover, CBG binding may enhance bioavailability under some conditions, as it represents a releasable Cortisol reservoir (Breuner & Orchinik, 2002). Because plasma Cortisol reflects both the free and bound fractions, this measure may not provide the most valid index of Cortisol tissue bioactivity under all conditions, despite the fact that plasma levels are often considered the gold standard of Cortisol measures.

As illustrated by the solid arrows in Figure 12.6, plasma Cortisol represents only one metric of HPAC activity. With regard to the issue of bound vs. unbound Cortisol, salivary Cortisol levels offer the advantage of indexing only the unbound fraction. This is because CBG and other proteins do not readily diffuse across cellular membranes. Consequently, protein-bound Cortisol does not readily enter the salivary glands, and salivary Cortisol levels reflect primarily the unbound fraction of plasma Cortisol. Salivary Cortisol levels are also noninvasive and can be obtained under a wider range of experimental conditions, including ambulatory studies. Although the time constant of Cortisol diffusion into salivary glands tends to dampen pulsatile patterns somewhat, salivary Cortisol can still show short-term pulse-related fluctuations. Time required to acquire an assayable saliva sample also tends to blunt, but does not eliminate, short-term fluctuations. Consequently, the time sampling issues raised earlier for plasma Cortisol levels also apply to salivary Cortisol measures.

A measure of Cortisol can be derived also from urine. Urinary Cortisol reflects the free, unbound fraction of plasma Cortisol, as protein-bound Cortisol does not readily enter the renal tubular system. Cortisol accumulates in the urine in proportion to plasma free-cortisol levels, and because of the general stability of this molecule, collection of urinary output can provide an integral index of Cortisol over extended (including daily) periods.

There is considerable debate as to what constitutes the best measure of HPAC activity, and there may be no single answer to this question. Rather, the validity of a measure may be defined by the problem under study. Urinary measures integrated over a day or more may be most relevant for studies of chronic stress. In contrast, shorter term measures such as those from plasma or saliva may be more useful for studies of acute stress or circadian rhythms.

Reciprocal influences between neurobehavioral and HPAC systems. In accord with the principle of Reciprocal Determinism, the HPAC system offers an illustration of the multiple interactions between neuroendocrine systems, neurobehavioral substrates, and psychological processes. Although physical stressors are known activators of the HPAC system (Selye, 1956), psychological stressors are among the most potent (Mason, 1968, 1975; McEwen, 2000). It is also clear that HPAC activity can impact both cognitive and emotional processes (e.g., Lupien & McEwen, 1997; Parker et al., 2003). Psychological states can alter HPAC activity, and HPAC activity can modulate the psychological states that gave rise to this activity. These reciprocal actions can be dose and context dependent. Glucocorticoid administration can either enhance or impair cognitive processes, as a function of dose, context, and the specific receptor populations activated (Lupien & McEwen, 1997).

Some of the complexity of these effects relate to the multiple reciprocal interactions within the HPAC system (e.g., CRH and Cortisol feedback) and between the HPAC and psychological processes (e.g., stress and Cortisol). Reciprocally interacting systems are difficult to study and characterize in isolation, as their functional outputs represent a close interplay across levels of organization. Consequently, manipulations at one point may have diverse effects throughout these circuits. The central CRH system, in addition to its regulation of pituitary ACTH release, is considered to be a general orchestrator of the cognitive, affective, behavioral, autonomic, and neuroendocrine aspects of stress. Local intracerebro-ventricular infusions of CRH in primates results in an activation of stress-related brain circuits, induces anxiety- and depressive-like reactions, and decreases social interactions (Strome et al., 2002). Because glucocorticoid administration alters central CRH activity, it is not immediately apparent whether the effects of this manipulation reveal the direct actions of glucocorticoids or indirect effects on CRH systems. Dissecting reciprocally interacting systems requires multiple experimental approaches and converging data that can provide a more comprehensive perspective than a more restricted analyses. Because interactions may never be known by studying hormonal systems in isolation, the corollary of interdependence asserts that the most meaningful studies will entail manipulations and observations of both CRH and Cortisol, involving a combination of methods.

Social psychological influences and the corollary of interdependence. Relations across levels are particularly difficult to conceptualize when the reciprocally interacting nodes extend across broad spans of organization or analysis, as the complexity of mappings tends to increase across more distal levels. A recent line of research in psychoneuroimmunology illustrates this. It has long been recognized that psychological stressors are potent activators of the HPAC system (Mason, 1968, 1975; McEwen, 2000). In contrast to the general adaptation model of Selye (1956), it further appears that there may be fundamental differences in kind among physical and social-psychological stressors. Social reorganization stress in mice (rotation of alpha males among housing colonies) can lead to reactivation of herpes simplex Type 1 virus (HSV1), similar to the stress-related HSV1 reactivation that causes cold sores in humans (Padgett et al., 1998). In contrast, physical stressors (e.g., restraint-stress or shock) are ineffective despite producing comparable glucocor ticoid levels. Subsequent work has revealed further unique characteristics of social stressors, highlighting the need for multilevel research and mandating expansion and refinements in the concept of stress and the nature of stressors.

Subsequent studies revealed that social stressors in mice are associated with an exaggerated and often lethal inflammatory response to influenza virus, compared to restraint stress (Sheridan, Stark, Avit-sur, & Padgett, 2000). The difference between the social and the physical stressors could not be accounted for by differences in secretion of antiinflammatory glucocorticoids, because both classes of stressors again yielded comparable glucocorticoid levels. Rather, it appears that social stress induced a state of glucocorticoid resistance or receptor insensi-tivity attributable to an impairment in nuclear translocation of the glucocorticoid/receptor complex in specific macrophages of socially stressed animals (Quan et al., 2003). As a result, glucocorticoids failed to suppress the actions of a transcription factor (NF-kappaB), which promotes the production of pro-inflammatory cytokines (interleukin 1 and tumor-necrotizing factor alpha). In this research, a bridge was established between social processes and gene expression in the health effects of stress.

These examples illustrate the principle of Reciprocal Determinism and its Corollary of Interdependence. Multilevel studies can elucidate influences across levels of organization and clarify relations that could not be known by studies limited to a single level of analysis.

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