One important modifier of the stress response is the degree to which a stressor is perceived as controllable (Maier and Watkins 2005). Animal studies have indicated that a sense of control is an important aspect of hardiness. Experiments have shown that animals with control over the amount of shock they received fared much better those deprived of control (Maier et al. 1969; Seligman and Maier 1967; Weiss 1968). Rats that lacked control of the shock they received ate less, lost more weight, developed more ulcers, had higher resting blood pressure and higher plasma cortisol, displayed less aggression in the face of an intruder, were less responsive on standard measures of pain sensitivity and reactivity, and had more immunosuppression (Maier and Watkins 1998); they also had changes in epinephrine in the locus coeruleus and hypothalamus (Weiss et al. 1981). Similar experiments in dogs (Chourbaji et al. 2005; Overmier and Seligman 1967; Vollmayr and Henn 2001) found that those given inescapable shocks failed to avoid later shocks even when they were able to, a behavior called learned helplessness.

The biologic mechanism that underlies how uncontrollable stress might lead to deficits in escape appears to be abnormal activation of two brainstem nuclei: the dorsal raphe nucleus and the locus coeruleus (Maier et al. 1995). Activation of neurons there leads to the release of the neurotransmitters serotonin and norepinephrine into almost all parts of the brain, where they modify cellular activity. However, the mechanism by which those primitive brainstem nuclei mediate the complex cognitive process required to judge the uncontrollability of a stressor has been unclear. It has recently been shown in rats that stress always activates the brainstem nuclei, but activation is inhibited by the prefrontal cortex, a brain structure that appears to be dysregulated in people with PTSD (see Chapter 5) (Amat et al. 2005). Thus, a dysfunctional prefrontal cortex in PTSD could perhaps exacerbate a feeling of being out of control. Animal studies illustrate the potential role of perception of control in the stress-response process.


Activation of the stress response ensures survival in the short term, but is maladaptive when its activation persists as a result of chronic, severe, or repeated stress. Chronic stress can lead to adverse health outcomes that affect multiple body systems such as the CNS and the endocrine, immune, gastrointestinal, and cardiovascular systems. Stress-induced abnormalities are due to dysregulation of a common set of mediators: cortisol, epinephrine, and immune-system cytokines. The model of stress-related illness is built on evidence of interrelationships between stress hormones and other systems, including the endocrine and immune systems. Stress hormones can trigger interactions between the endocrine and immune systems that culminate in a state of chronic inflammation. Stress-induced chronic inflammation appears to be a driving force behind wide-ranging conditions linked to stress, such as obesity, heart disease, diabetes, and chronic pain (Black and Garbutt 2002; Black et al. 2006; Malarkey and Mills 2007). Research on the role of inflammation with the CNS is focusing on interrelationships between immune cells, cytokines, and nearby neurons situated in regions of the brain implicated in stress-related disorders (MacPherson et al. 2005).

This section reviews some of those adverse health effects; in many cases, they are markers of disease or symptoms rather than specific diseases.

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