340 Chapter 11
(structures of the limbic system; chapter 8, section 8.2). These
higher brain regions influence stress responses through synapses
in the hypothalamus, medulla oblongata, and spinal cord. The
hypothalamus-anterior pituitary-adrenal axis, with rising levels
of glucocorticoids, becomes more active when the stress is of a
chronic nature and when the person is more passive and feels less
in control.
In rodents, the positive stress of social interactions and an
enriched environment promote health and recovery from ill-
ness, whereas chronic negative stress has the opposite effects,
perhaps due to glucocorticoid suppression of the immune
system. Such negative stress can promote tumor growth in
rodents, and similar responses have been reported in humans.
Experiments in mice also suggest that glucocorticoids released
during the stress of repeated aggression promote the anxiety
and social aversion that develops.
There is also a dichotomy in the effects of stress on memory.
Brain regions involved in memory (the prefrontal cortex, hippo-
campus, and amygdala) have receptor proteins for the stress hor-
mones (glucocorticoids, epinephrine, and CRH), and these have
been demonstrated to both promote and suppress LTP and LTD
(long-term potentiation and depression, respectively; chapter 8,
section 8.2). On the one hand, glucocorticoids and epinephrine
can enhance LTP and memory formation during acute stress. On
the other hand, high amounts of glucocorticoids released dur-
ing chronic stress inhibit LTP in the hippocampus, amygdala,
and prefrontal cortex. These synaptic changes may relate to the
disruption of working memory (a function of the prefrontal cor-
tex) and declarative memory (a function of the hippocampus)
by stress. The stress hormones may also act on the amygdala
(important for the encoding of fearful memories) and other brain
regions to contribute to the anxiety and depression associated
with prolonged negative stress.
Glucocorticoids stimulate catabolism, chiefly the break-
down of muscle protein and fat. At the same time, they stimulate
the liver to convert amino acids to glucose (in a process termed
gluconeogenesis ), leading to a rise in blood glucose concentration.
These actions are described in detail in chapter 19, section 19.5.
Through these and other effects, the glucocorticoids antagonizeStress and the Adrenal Gland
In 1936 a Canadian physiologist, Hans Selye, discovered that
injections of a cattle ovary extract into rats (1) stimulated growth
of the adrenal cortex; (2) caused atrophy of the lymphoid tis-
sue of the spleen, lymph nodes, and thymus; and (3) produced
bleeding peptic ulcers. At first he attributed these effects to the
action of a specific hormone in the extract. However, subsequent
experiments revealed that injections of a variety of substances—
including foreign chemicals such as formaldehyde—could pro-
duce the same effects. Indeed, the same pattern occurred when
Selye subjected rats to cold environments or when he dropped
them into water and made them swim until they were exhausted.
The specific pattern of effects produced by these procedures
suggested that the effects were due to something the procedures
shared in common. Selye reasoned that all of the procedures were
stressful, and that the pattern of changes he observed represented
a specific response to any stressful agent. He later discovered that
these effects were produced by activation of the pituitary-adrenal
axis. Under stressful conditions, there is increased secretion of
ACTH from the anterior pituitary, and thus there is increased
secretion of glucocorticoids from the adrenal cortex.
On this basis, Selye stated that there is “a nonspecific
response of the body to readjust itself following any demand
made upon it.” Stress causes a rise in the plasma glucocorti-
coid levels. Selye termed this nonspecific response the general
adaptation syndrome (GAS). Stress, in other words, produces
GAS. There are three stages in the response to stress: (1) the
alarm reaction, when the adrenal glands are activated; (2) the
stage of resistance, in which readjustment occurs; and (3) if
the readjustment is not complete, the stage of exhaustion,
which may lead to sickness and possibly death.
For example, when a person suffers from the stress of severe
infections, trauma, burns, and surgery, the cortisol level can rise in
proportion to the severity of the stress to as high as six times basal
levels. There is evidence that this response of the pituitary-adrenal
axis is needed for proper recovery from the illness or trauma, per-
haps because cortisol and other glucocorticoids inhibit the immune
response, thereby reducing damage due to inflammation. Thus,
severe infections and trauma that trigger an immune response also
activate mechanisms (the adrenal’s secretion of cortisol) to limit
that immune response. Indeed, patients who cannot secrete an ade-
quate amount of cortisol for different reasons have an increased
risk of death during an illness or trauma.
The sympathoadrenal system becomes activated, with
increased secretion of epinephrine and norepinephrine, in
response to stressors that challenge the organism to respond phys-
ically. This is the “fight-or-flight” reaction described in chapter 9,
section 9.3. Hans Selye distinguished between neutral or positive
stressors (which are “eustressful”) and negative stressors (which
are “distressful”), and modern research has confirmed that these
differ in their neuroendocrine responses. This leads to the view
of stressors as anything that disrupts homeostasis. The different
responses of the pituitary-adrenal axis and sympathoadrenal sys-
tem to different stressors are coordinated by higher brain regions,
particularly the prefrontal cortex, amygdala, and hippocampus
CLINICAL APPLICATION
Exogenous glucocorticoids —including prednisone, pred-
nisolone, and dexamethasone —are used medically to
(1) suppress the humoral and cell-mediated portions of the
immune system, and (2) suppress inflammation that may
result from many causes. For these reasons, they are widely
used for the treatment of asthma, autoimmune diseases,
and many other conditions. They are also used to suppress
the immune rejection of transplanted organs. Exogenous
corticosteroids, through negative feedback, suppress the
secretion of pituitary ACTH and thus can lead to atrophy
of the adrenal cortex. This is why the use of these drugs
should be tapered off rather than stopped abruptly.