Which of the following is not the stage of general adaptation syndrome

3 Energy Mobilization and Anabolism at Work

In Selye's (1976) general adaptation syndrome, ‘stress’ was seen as the general reaction to a nonspecific challenge or adverse condition. The situation that induced stress was labeled a stressor (factor which induces stress). Since this has central importance to the understanding of stress at work, a short description of the energy mobilization will be given here. The most important biological process is the provision of energy—glucose and free fatty acids enter the blood, and these are used for the immediate production of energy. But there are several parallel phenomena, all of which aid the body in the physical fight or flight. Examples are lowered excretion of water and salt, decreased sensitivity to pain, and decreased inflammatory responses to infections. Since energy mobilization (resulting in elevated blood concentration of glucose and free fatty acid) has the highest priority, anabolism (restorative and regenerative activities in the cells) is down regulated. Anabolism is central to the body's central defense of all the organ systems that need constant rebuilding and restoration. If this goes on for a long time (several months) increased sensitivity to physical and psychological stress in bodily organs is the ultimate result.

Another consequence of long-lasting demands for energy mobilization is that the endocrine systems may change their regulatory patterns. This means that the ability of the body to stop energy mobilization when it is no longer needed may be disturbed or that the counter-regulation (inhibition of energy mobilization) is inhibited. Most processes in the body have a counter-regulatory mechanism that operates in order to inhibit a process that has been stimulated.

General Adaptation Syndrome

Selye first put stress on the map with GAS. In search of a new hormone, Selye injected extracts of cattle ovaries into rats. The injection caused the following characteristic triad:

The adrenal cortex became enlarged and discharged lipid secretory granules.

The thymus, spleen, lymph nodes, and all other lymphatic structures showed severe involution.

Deep bleeding ulcers appeared in the stomach and duodenum.

Selye at first thought that these effects were due to a new hormone in the extracts but soon found that all toxic substances – extracts of kidneys, spleen, and even toxicant not derived from living tissue produced the same syndrome.

Selye surmised that the response to the injection of toxic substance reflected his “classroom concept” of “the syndrome of just being sick.” That is, adrenal enlargement, thymicolymphatic involution, and gastrointestinal ulcers were the omnipresent signs of damage to the body when under attack. The three changes thus became (for Selye) the objective indices of stress and the basis for the development of the entire stress concept.

First described in a note to Nature in 1936, GAS has three stages: alarm, resistance, and exhaustion. In the alarm stage, the body shows changes characteristic of the first exposure to the stressor; these changes generally coincide with the sympathetic discharge that enables the fight-or-flight phenomenon of Cannon. If the stressor continues and is compatible with adaptation, features of the alarm reaction disappear and resistance develops. Prolonged exposure to the stressor may result in exhaustion and finally death.

One of the most important findings of GAS is the stress-induced thymicolymphatic involution, which highlighted for the first time that stress has a major impact on the immune system. This concept preceded by more than 20 years the discoveries of lymphocyte recirculation by James Gowans and acquired immunological tolerance by MacFarlane Burnet and Peter Medawar. Selye’s discovery began the field of neuroimmunomodulation.

Selye soon became aware of the fact that the adrenal enlargement of GAS was associated with increased secretion of glucocorticoids (cortisol or corticosterone) that

induce glycogenolysis, thereby supplying a readily available source of energy for the adaptive reactions necessary to meet the demands made by the stressors. In addition, they facilitate various other enzymatically regulated adaptive metabolic responses and suppress immune reactions as well as inflammation, assisting the body to coexist with potential pathogens.

Selye asserted that glucocorticoids are needed for adaptation to stress primarily during the alarm reaction. Selye’s view that glucocorticoids enhance and mediate the stress response has been upheld with the additional concepts that glucocorticoids play a permissive role that primes the body’s stress response systems and also prevent overshoot of the defense systems. Overshoots in the body’s defense system are perhaps most dramatically seen in major inflammatory cataclysms called cytokine storms and the consequent systemic inflammatory response syndromes that play a key role in the lethality of avian influenza and have also occurred in response to the injection of certain antibodies. Exogenous synthetic glucocorticoids such as methylprednisolone remain a mainstay of the treatment of cytokine storms.

Although GAS is sometimes manifest in extreme stress, the three components of GAS have not withstood the test of time as indices of stress as Selye had originally proposed. Rather, the main biological markers of stress have long been behavioral observations and tests and measures of sympathetic and HPA activation. In the case of the latter measurements of glucocorticoid concentrations in blood, either alone or in parallel with plasma concentrations of ACTH, have been used as the main biological indices of stress. So, despite its heuristic value, especially for stress-induced neuroimmunomodulation, the concept of GAS has lost scientific currency.

Effect of Chronic Stress

According to Selye, “the imperfections of the adaptation syndrome”7 coincide with an altered balance in adaptive hormones and are important in the pathogenesis of most stress-related diseases. Selye referred in this context to the pendulum hypothesis, where excess mineralocorticoid over glucocorticoid enhanced vulnerability to inflammation whereas the reverse enhanced risk of infection.1 Chronically stressed animals show profound changes in neuroendocrine regulations due to an altered phenotype of the CRH neurons expressing much more vasopressin as co-secretagog54 and profound changes in brain plasticity.3

In animal experiments using dentate gyrus (where neurogenesis occurs) of controls 26 different GO terms could be assigned in pathway analysis, but the diversity in the CORT responsive pathways was in the stressed group reduced to only 7. After chronic stress, CORT or acute stress induced particularly genes involved in chromatin modification, epigenetics, and the cytokine/NFκB pathway.55 One highly responsive gene network revealed by this procedure is the mammalian target of rapamycin (mTOR) signaling pathway which is critical for different forms of synaptic plasticity and appears to be associated with depression.

Since CORT challenge was used to identify dysregulated pathways in limbic regions of the chronically stressed animals, it may also represent a target for treatment. Indeed, enhanced expression of MR locally in the hippocampus or amygdala was protective to the effect of stress. Reduced MR expression is observed during the aging process56 and depression.57 Furthermore, in such stressed animals blocking GR with an antagonist improved cognitive performance,7,58 reversed suppression of neurogenesis, Ca current and long term potentiation (LTP),5 and rescued the CREB-signaling pathway.59 Antiglucocorticoid treatment or genetic deletion of GR after chronic stress restored the hyperactive dopaminergic mesolimbic/cortical-amygdala loop and social behavior.60

Stress Reaction

The stress reaction is defined by Hans Selye in his general adaptation syndrome model (Figure 1). Each of the stages in this model – alarm, resistance, and exhaustion – involves the body's neuroendocrine system, which is influenced by psychological and physical stimuli.

Alarm, fight or flight, is the immediate response of the body to ‘perceived’ stress. Physiologically, this starts at the brain's hypothalamus, which acts as the central computer chip of the body regulating such functions as heart rate, blood pressure, respiration, body temperature, digestion, hunger, thirst, and libido. Surrounding the hypothalamus is the limbic system, one of the oldest parts of the brain, which houses the emotions. Powerful feelings such as fear and rage trigger the hypothalamus, which sends messages to the autonomic nervous system by the hypothalamic–pituitary–adrenal (HPA) axis and separately through the autonomic nervous system. The nerves of the autonomic nervous system are split into either parasympathetic or sympathetic branches, the latter of which causes an immediate stress reaction by releasing catecholamines (adrenaline-like chemicals). These chemicals released from the adrenal gland increase heart rate, respiration, and blood pressure.

The activated hypothalamus also secretes its own hormones and stimulates the pituitary gland to secrete hormones, which produce some of the same effects as those of the catecholamines but which last some 10 times longer and have a far wider reach. One of these hormones, corticotropin-releasing hormone (CRH), is sent to the pituitary to trigger the release of adrenocorticotropin hormone (ACTH). ACTH travels through the bloodstream to the adrenal glands, on top of the kidneys, to produce glucocorticoids (such as cortisol), which start a cascade of events, including increased blood glucose concentrations, elevated blood pressure, and slowed digestion (Figure 2). Specifically, insulin's ability to facilitate glucose uptake by the cells is reduced, while gluconeogenesis, the synthesis of new glucose (from glycerol and amino acids) is increased. Blood pressure rises as the kidneys are signaled to retain more sodium, which raises water volume in the blood vessels. Also, digestion slows as hormonal changes cause muscles to become engorged with oxygen and glucose-rich blood that is shunted away from the digestive tract. The body in this conditional response to stressors is ready for fight or flight. (See HORMONES | Pituitary Hormones.)

Resistance (adaptation), the second stage of the stress response, is to achieve optimal adaptation in resisting the stressor. Everyday stressors (eustressors) are beneficial in maintaining the psychophysiological balance that results when the stressor is successfully removed, adapted, or coped with by the person. Stress is actually a necessary component in life because it contributes to survival and, ultimately, growth. Optimal stress fuels maximum performance, but excess stress results when the demands on a person exceed or fall far below their capabilities. Hans Selye said the only time an individual is free from stress is death – the ultimate flight. However, too much stress, and failure to adapt and reach a healthy homeostasis, can also result in illness or death.

Exhaustion, the last stage of the stress response, a continued, chronic response to stress, can be a risk factor for many multifactorial disorders. These in turn may lead to a downward spiral of more stress, exhaustion, and possibly extinction. Eustress becomes distress if not adequately handled by the body and mind (Table 3). Physical and psychological well-being become ‘ill,’ decreasing the quality of life, if not its very presence.

Table 3. Factors and feelings associated with eustress and distress

EustressDistressIncreased mental acuityForgetfulnessDiminished attention to detailPoor work performancePleasure/happinessSadnessEmotional outburstsEuphoriaLethargy, apathy

Modified from Clancy J and McVicar A (1993) British Journal of Nursing 2(8): 410–417.

While the changes produced by stress-initiated hormones are beneficial in the short term, they can be detrimental when prolonged. It is now generally believed that most signs and symptoms of stress-related disease are the result of stress hormones marshaled by the hypothalamus in response to an alarm for which their particular actions are no longer appropriate.

Selye's Definition of Stress – a Further Consideration

As intimated above, Hans Selye was the first to use the word stress in the context of biomedicine, and define the concept and phenomenon of stress in a generic and non-specific manner. Selye's definition and concept of stress has remained controversial. For some, his definition is too biological and ignores cognitive and psychological factors, a criticism that seems to stem from the mistaken idea that cognition is not brain/biologically based (a reversion to Rene Descartes' outmoded doctrine that mind and body are separate). For others, Selye's definition is too general. Selye systematically rebutted some of these and other criticisms (Selye, 1975). Here we review the basis for Selye's definition of stress, and consider whether the criticisms leveled at Selye's stress concept are valid. Overall, our observations suggest that Selye fully understood so-called psychological or cognitive stress, and that the generality of Selye's stress definition has facilitated the molecular, genotypic and phenotypic analysis of stress and stress responses across all species from bacteria to man.