as cortisol, is present in excessive or insufficient amounts, other mediators are also changed. Over the course of days, weeks, and longer, allostatic load eventually can disrupt health, a condition called allostatic overload or toxic chronic stress response. Allostatic overload is maladaptive: it serves no useful purpose and predisposes the body to disease.

Allostatic load and allostatic overload are points on a continuum. The pattern, frequency, and duration of stressors are important determinants of the severity of the outcome, as are a person’s response to the stressors. Four types of physiologic responses lead to allostatic load and overload (Figure 4-3). Two of them are related to individual differences in the stress response: prolonged response (B) and inadequate response (C). The other two are related to chronic stressor characteristics: repeated exposure (D in the figure) and lack of adaptation (E). Initially, the health consequences of allostatic load or overload are early indicators of possible later disease, such as hypertension, obesity, increased cholesterol, bone mineral loss, muscle protein loss, memory impairment, and increased anxiety.


Many factors may alter a person’s response to stress, including genetic makeup, early-life history, and the degree to which the stressor can be controlled. Research is under way on all those, primarily in animal models. Each is discussed below.


Many aspects of the stress response—such as learned and innate fear (see, for example, Shumyatsky et al. 2005), reward, social behavior, and resilience (Charney 2004)—are likely to be under the influence of particular genes. Genes determine which proteins will be made and where they will be made. The same gene might have slightly different sequences (alleles) that alter the protein production. An example of allelic variation occurs in the gene that codes for the serotonin-transporter protein. That protein removes serotonin—a chemical messenger in the brain that affects emotions, mood, behavior, and thought—from the synaptic cleft between nerve cells after it is released by a presynaptic cell. A short allele makes less of this protein than the long allele found in most people, thus altering serotonin transmission (Hariri et al. 2006). In some studies, people with the short allele are prone to more anxiety and more likely to acquire conditioned fear responses (Hariri et al. 2006). Furthermore, they are more likely to develop depression but only if they were maltreated in childhood (Caspi et al. 2002). Thus, just having the short allele does not necessarily lead to depression, but combined with early life stress it can increase the risk of depression. Conversely, people with the longer allele (and higher levels of serotonin transporter) were less likely to develop depression even if they had been maltreated in childhood; the longer allele protected them. That is an example of gene-environment interactions in which a medical condition cannot be predicted only by a gene or only by a serious life event but requires a combination of a genetic factor and an environmental event for the outcome to occur.

Researchers have investigated the mechanisms that might explain such gene-environment interactions. For example, Ichise et al. (2006) examined the same interactions between a short serotonin-transporter allele and exposure to early-life stress in rhesus monkeys. Monkeys reared by peers rather than by their mothers—a stressful condition—showed a decrease in serotonin

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