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Mechanisms of Stress: A Dynamic Overview

of Hormonal and Behavioral Homeostasis

E L I Z A B E T H O. J O H N S O N , * t t T H E M I S C. K A M I L A R I S , * t G E O R G E P. C H R O U S O S * A N D P H I L I P W . G O L D t

*Developmental Endocrinology Branch, National hlstitute o f Child Health and Human Development and
"~Clinical Neuroendocrinology Branch, National hzstitute o f Mental Health, NIH, Bethesda MD 20892

R e c e i v e d 13 D e c e m b e r 1990

JOHNSON, E. O., T. C. KAMILARIS, G. P. CHROUSOS AND P. W. GOLD. Mechanisms of stress: A dynamic overview of
hormonal and behavioral homeostasis. NEUROSCI BIOBEHAV REV 16(2) 115-130, 1992.-Environmental events, both physi-
cal and emotional, can produce stress reactions to widely varying degrees. Stress can affect many aspects of physiology, and
levels of stress, emotional status, and means of coping with stress can influence health and disease. The stress system consists of
brain elements, of which the main components are the corticotropin-releasing hormone (CRH) and locus ceruleus (LC)-norepi-
nephrine (NE)/autonomic systems, as well as their peripheral effectors, the pituitary-adrenal axis and the autonomic system, which
function to coordinate the stress response. Activation of the stress system results in behavioral and physical changes which allow
the organism to adapt. This system is closely integrated with other central nervous system elements involved in the regulation of
behavior and emotion, in addition to the axes responsible for reproduction, growth and immunity. With current trends in stress
research which focus on understanding the mechanisms through which the stress-response is adaptive or becomes maladaptive,
there is a growing association of stress system dysfunction, characterized by hyperactivity and/or hypoactivity to various patho-
physiological states. The purpose of this review is to 11 define the concepts of stress and the stress response from a historical
perspective, 2) present a dynamic overview of the biobehavioral mechanisms that participate in the stress response, and 3) exam-
ine the consequences of stress on the physiologic and behavioral well-being of the organism by integrating knowledge from appar-
ently disparate fields of science.

Stress HPA axis Autonomic system Aging Reproductive suppression Growth retardation
Immunosuppression Depression

DEFINITION OF STRESS
A critical problem faced by investigators lies in the defini-
tion of stress and related concepts (Table 1). The term " s t r e s s "
describes a state of threatened "homeostasis" (Greek for "'steady
state") or threatened harmony, balance, or equilibrium. The
threatening, disturbing forces are defined as "'stressors,'" while
the counteracting forces put forth to neutralize the effects of the
stressors and reestablish homeostasis are called the "'adaptive
response" (42). A major problem in stress biology is confusion
regarding the definitions for " s t r e s s , " "stressor," "'adaptive re-
sponses," and "consequences of stress."
Historical Development of Stress as a Concept
The concept of "homeostasis" goes back to the ancient
Greeks (Table 2). The natural philosopher Empedocles consid-
ered that all matter was a harmonious mixture of elements and
qualities (42,65). This early expression of homeostasis was ex-
tended to living beings by Hippocrates, who considered health
as the state of harmonious balance, and disease as the state of
dysharmony (3). Hippocrates described disturbing forces of na-
ture as causes of disease and referred to the healing forces in-
herent to the organism as the "healing power of Nature." This
was later called by Galen "vis medicatrix Naturae.'" Psychogenic
stress was mentioned by Epicurus, who suggested that coping
with emotional stressors was a way to improve the "quality" of
life (42,65).
In the early nineteenth century, the French physiologist Claude
Bernard introduced a theory suggesting that, as organisms be-
come more independent of their surroundings, they develop
more complex ways of stabilizing their internal environments to
counter the changes in their external environment. The impor-
tance of adaptive mechanisms was thus recognized as the con-
stancy of the "milieu interieur,- which would be the condition
of a free and independent existence (18).
In the early 1900's, Walter Cannon expanded this theory and
coined the term "homeostasis." He demonstrated in several
seminal experiments that the sympathoadrenal system was re-
sponsible for coordinating the "fight or flight" response neces-
sary to meet external challenges (27). Cannon was able to show
that both physical and emotional disturbances triggered the same
response from the organism. In addition, he proposed that there
was a "critical" level of stress, in terms of magnitude and du-
ration, against which the homeostatic mechanisms fail and the
organism perishes. Cannon believed that an individual organ-
ism's susceptibility to this critical stress "varied under different

tRequests for reprints should be addressed to Elizabeth O. Johnson, Developmental Endocrinology Branch, National Institute of Child Health and
Human Development, NIH, Bldg. 10, Room 10N262, Bethesda, MD 20892.

115
116
TABLE 1
THE CONCEPT OF HOMEOSTASIS
Disturbing Harmony Counteracting
Forces ~ Balance ~: Neutralizing
Equilibrium Forces
Homeostasis
(Steady State)
II
Stressors ~
II
Threatened ,c
II
Adaptive
Homeostasis Responses
(stress)
general conditions and during the normal and pathologic ups and
down of existence in an ordinary life-cycle" (27).
In 1936, Selye presented his concept of the "General Adap-
tation Syndrome," and attention shifted from the sympathetic
nervous system to the adrenal glands (183). Selye defined four
stages of the stress reaction: 1) an initial "alarm reaction,"
characterized by an immediate sympathoadrenomedullary dis-
charge; 2) a "stage of resistance," characterized by activation
of the hypothalamic-pituitary-adrenal (HPA) axis; 3) a stage of
adrenal hypertrophy, gastrointestinal ulceration, and thymic and
lymphoid shrinkage, which he called the "General Adaptation
Syndrome"; and 4) a final stage of exhaustion and death.
Chronic alterations in the hormonal responses and abnormal
changes in several tissues were believed to cause the "diseases
of adaptation" (184,187).
Hams, a contemporary of Selye's, suggested in 1948 that
hypothalamic releasing or inhibiting factors regulate anterior pi-
tuitary function (83). Saffran and Schally demonstrated in 1955
that a factor from the hypothalamus was regulating ACTH re-
lease from the pituitary (166). They named this principle "corti-
cotropin-releasing factor." After intensive investigation, in 1981,
Vale and others were able to isolate this factor and characterize
its structure as a 41 amino-acid peptide (207). When the chemi-
cal structure was identified, the term "factor" was changed to
"hormone."
Contemporary theory in stress biology conceptualizes an in-
tegrated "stress system" consisting of neuroanatomical and func-
tional structures that function to produce the behavioral,
physiological and biochemical changes directed toward maintain-
ing homeostasis (42). This theory is supported by recent find-
ings in neurobiology demonstrating anatomical and functional
connections between the hypothaiamus, the arousal center in the
pons, and several sympathetic nuclei in the hindbrain (26, 141,
209). In the periphery, the adrenocortical and sympathetic divi-
sions of the stress system have additional integrative actions.
These include complementary and permissive interactions of
glucocorticoids and catecholamines in the regulation and mainte-
nance of metabolic and cardiovascular homeostasis (22,157).
Classification of Stressors--The Adaptive Response to Stress
The adaptive response to stress appears to depend upon the
quality (physical or emotional), strength, and duration (acute,
chronic) of the stimulus, as well as upon the constitution and
state of the organism (51). A stressor can be viewed as any per-
turbation that disrupts homeostasis. Physical stressors include
disturbances of the internal environment (anoxia, hypoglycemia,
etc.), external extremes (heat and cold), and multifaceted stres-
sors (noxious stimuli and physical strain, such as exercise or in-
JOHNSON, KAMILARIS, CHROUSOS AND GOLD
TABLE 2
HISTORY OF THE CONCEPT OF STRESS
Empedocles first written reference to homeostasis.
(500--430 BC)
Hippocrates Health is the state of the harmonious balance of the
(460-375 BC) elements, and disease is the state of
dysharmony."Nature heals disease" (Noysvn Fyseiw
Iatroi).
Epicurus
(341-270 BC)
Coping with emotional stressors improves the quality
of life.
Claude Bernard "Milieu interieur."
(1813-1878)
Walter Cannon "Fight or flight" reaction; "homeostasis."
(1871-1945)
Hans Seyle The "General Adaptation Syndrome."
1907-1982)
jury). Psychological stressors are stimuli that affect emotion and
result in fear, anxiety, or frustration, and are among the most
potent activators of the HPA axis (113, 124, 185). It should be
noted that stressors may be mixed and act in combination.
The adaptive response to stress includes the behavioral and
physiological processes that the organism consistently musters in
its attempt to reestablish homeostasis in the face of a wide range
of stressors (183,186). In general, the adaptive response to stress
involves a redirection of both behavior and energy (43) (Table
3). Behavioral adaptation is viewed as the facilitation of adap-
tive, and inhibition of nonadaptive, neural pathways which en-
able the organism to cope more successfully with the stressful
stimulus. These behavioral responses include altered cognitive
and sensory thresholds, increased alertness, selective memory
enhancement (27), stress-induced analgesia (204), and suppres-
sion of feeding and reproductive behavior (28,191). Peripheral
adaptation is viewed as provision of the energy necessary to
overcome stressors and involves both a shift of energy substrates
from storage sites to the bloodstream, as well as appropriate
cardiovascular changes. Glucocorticoids, epinephrine (E), and
norepinephrine (NE) act to inhibit glucose uptake, fatty acid
storage, and protein synthesis at storage sites and stimulate the
release of energy substrates, including glucose, amino acids, and
free fatty acids, from muscle, fat tissue and liver (133,218).
These changes in energy availability are paralleled by the stimu-
lation of cardiovascular and pulmonary function, which include
increased heart rate, blood pressure and respiration (218). Simul-
taneously, anabolic processes, such as digestion, growth, repro-
duction and immune function, are suppressed (105).
It appears that the ability to appropriately regulate the stress
response may be as important as the ability to initiate it. Con-
tainment of the stress response is crucial to avoid the behavioral
and physical consequences of the mobilization of behaviors and
resources. Chronic activation of the catabolic processes of the
stress response can ultimately become destructive and patho-
genic. Thus metabolic (myopathy, fatigue, changes in glycemia)
and cardiovascular consequences (hypertension), compromised
growth and tissue repair, peptic ulceration, reproductive suppres-
sion (impotence and amenorrhea), as well as consequences of
immunosuppression (increased susceptibility to infection and can-
cer) can occur when the state of stress is unduly prolonged
(105). In addition to elimination of, or habituation to, the stres-
sor, the containment of the stress response is assisted by various
stress-induced substances. Thus, for example, glucocorticoids
and opioids suppress both the HPA axis and the central sympa-
MECHANISMS OF STRESS 117

TABLE 3 Psychogenic/
BEHAVIORAL AND PHYSIOLOGICAL ADAPTATION Emotional Diurnal
DURING STRESS Stimuli Rhythms
Behavioral Adaptation
• Altered cognition and attention span level
• Increased alertness
Traumatic ~
/ Pressure.Sensitive
• Altered sensory threshold
Stimuli ~ \
/ //BaroreceptorSignals
• Sharpened memory and sensation
• Stress-induced analgesia
// / Cytokines/
• Suppression of feeding behavior / ,/ J Mediatorsof
• Suppression of reproductive behavior ACT_.H ~ / / / n ^ nflammation
Peripheral Adaptation ( ~ I - 1 3 - E P " "/6 -~.//E
• Oxygen and nutrients directed to the CNS and stressed body sites H /~~'-'-''"NE/NPY
• Detoxification from toxic products ~~CRH~ ~.,~"~ 5HT
• Altered cardiovascular tone
• Containment of the stress-response fI - / ,,~ " GABA/BZD
I /
I /
thetic system, while centrally produced norepinephrine inhibits
the sympathetic system via local a2-adrenergic receptor inhibi-
tion (203).
/ Pituitary
Although there is a stereotypic consistency of the responses \ //
that the body activates during stress, all stressors do not result
in identical profiles of behavioral and peripheral responses.
These differences appear to be related to genetic constitution, as
well as to early-life experiences (112, 163,200). Moreover, not \ ~\ ACTH
all stressors should be construed as noxious or injurious. Indeed,

many stressors promote essential differentiation, growth, and
enhanced physiological and behavioral competence, which would
be markedly impaired in a relatively stress-free environment. On
the other hand, in the context of constant or inescapable stress,
or in an organism in which the usual counterregulatory elements
of the stress response are relatively inoperative, the effectors of
the generalized stress response could produce secondary changes
that interfere with adaptation, rather than promote it (181, 182,
2 1 3 , 2 1 4 ) . An analogy to this situation of an unrestrained or ex-
cessive stress response is that of the spectrum of autoimmune
diseases that occur as a consequence of excessive stimulation of
the immune response or its escape from its usual counterregula-
tory elements (194-196).
Homeostasis and the Components of the Stress Response
The HPA axis and the sympathetic system are important reg-
ulators of an animal's homeostatic functions (205). Thus the or-
ganism's response to stress is composed of behavioral, endocrine,
and autonomic components, coordinated to neutralize the dis-
rupting effects of the "stressors" on homeostasis (42, 73, 74).
Below, we describe the mechanisms by which the various com-
ponents of the stress system restore homeostasis.
MECHANISMS OF THE STRESS RESPONSE
Hypothalamic-Pituitary-Adrenal (HPA) A.ris
The function of the HPA axis has been the subject of intense
basic and clinical research which has attempted to understand
why glucocorticoids are critical for life. The response to stress
is associated with increases in the levels of plasma glucocorti-
coids. The secretion of glucocorticoids from the adrenal cortex
is under the control of ACTH, which in turn is released from
the anterior lobe of the pituitary. ACTH secretion is regulated
by corticotropin-releasing hormone (CRH) and other secreta-
Glucocorico //
Adrenal
FIG. 1. Schematic representation of the putative regulation of the hypo-
thalamic-pituitary-adrenal (HPA) axis. The corticotropin-releasing hor-
mone (CRH) system is the principal central biologic effector which
facilitates a characteristic behavioral and peripheral response to stress.
CRH stimulates secretion of both hypothalamic and pituitary POMC
gene-derived peptides, the latter resulting in glucocorticoid secretion.
The activation of the CRH neurons appears to be regulated by central
stimulatory and inhibitory inputs and by multiple negative feedback
loops. (Solid lines represent stimulatory effects; broken lines represent
inhibitory effects.) The latter include an ultrashort CRH-mediated loop,
a short hypothalamic POMC gene-derived peptide loop, including both
ACTH and [3-endorphin, and a long glucocorticoid-mediated feedback
loop.
gogues from the hypothalamus (99, 133, 218) (Fig. 1).
Glucocorticoids exert many different effects, including effects
on cardiovascular function, metabolism, muscle function, behav-
ior and the immune system (43). These effects can be grouped
into two categories defined as permissive and regulatory (88).
"Permissive" effects of glucocorticoids function to " p e r m i t "
other hormones or factors to accomplish their function at a nor-
mal level, and are observed primarily in the resting state and
may span the resting and stress states. The permissive role of
glucocorticoids is crucial for maintenance of homeostasis at the
basal state (31, 103, 134, 157, 206). "Regulatory" effects of
glucocorticoids are exerted only by stress-induced levels of these
hormones. It has been hypothesized that the regulatory effects
of stress-related elevations of glucocorticoids may be necessary
118
to prevent overreaction of the central stress, immune and other
systems, which, if unchecked, lead to injury (133).
Several closed feedback mechanisms regulate the secretion of
glucocorticoids (99, 133, 218) (Fig. 1). There is a major feed-
back loop between glucocorticoids and the hypothalamic-pitu-
itary axis. Thus circulating glucocorticoids act on the pituitary
directly to inhibit ACTH secretion, and on the hypothalamus to
suppress secretion of CRH (99). Additional feedback loops in-
clude the inhibitory effects of ACTH, [3-endorphin ([3-EP) and
CRH on the hypothalamic CRH neuron (34). These mechanisms
enable the organism to maintain a stable blood level of gluco-
corticoids at all times, while simultaneously providing an emer-
gency override, via the central nervous system (CNS), to respond
to stressors.
Corticotropin-Releasing Hormone ( CRH)
It has long been recognized that the endocrine response to
stress is coordinated at the CNS. CRH is a 41 amino-acid pep-
tide secreted from the hypothalamus and has a putative role in
regulating the normal response to stress. The chemical isolation
and description of CRH by Vale provided an important missing
link in the system (207). The genes encoding the CRH molecule
in the human, rat and sheep have been characterized (157, 178,
189, 207). These genes have been highly conserved throughout
evolution. In fact, the CRH peptides from humans and rats are
identical in amino acid sequence (157,189). The existence of
CRH has been known since the 1950's, but synthetic CRH only
became available recently; the availability of synthetic CRH has
opened new experimental avenues.
Anatomical distribution. CRH, localized by immunocyto-
chemistry, is found in neuronal cell bodies in the paraventricular
nucleus (PVN) (26,141). CRH neurons project to the median
eminence, where they terminate on the capillaries of the hy-
pophyseal portal vessels. These vessels function as a direct short
vascular pathway from the hypothalamus to the anterior pitu-
itary. Thus CRH, which is released into the hypophyseal portal
system, is transported to the anterior pituitary, where it stimu-
lates pituitary corticotrophs to both synthesize and secrete ACTH.
A different set of PVN CRH neurons send projections to the
hindbrain, where they stimulate the electrical activity of their
target neurons in the arousal and sympathetic centers (208).
There also are extrahypothalamic CRH neurons. Through im-
munocytochemical, receptor studies and the detection of CRH
mRNA, CRH has been demonstrated in the brainstem, midbrain,
striatum, hippocampus, cerebral cortex, spinal cord, sympathetic
ganglia and adrenal gland (47,199). The broad distribution of
CRH and its receptors in the CNS provides a substrate for the
wide-ranging behavioral effects of this peptide.
Receptors. The CRH receptor is highly concentrated in the
brain, anterior pituitary, adrenal medulla and sympathetic gan-
glia of the rat and several primates (45,209). CRH receptors in
pituitary corticotrophs appear to be sensitive to circulating levels
of glucocorticoids, as these receptors decrease shortly after adre-
nalectomy or during chronic stress (6,217). These conditions are
associated with increased hypothalamic CRH and vasopressin
(AVP) secretion, and decreased responsiveness to physiologic
increases in plasma glucocorticoids, respectively.
Regulation. CRH secretion can be affected by stimuli such
as emotion, pain and changes in blood pressure. The PVN has
connections with various components of the limbic system, im-
plicated in emotions, such as fear, and anger. Pain pathways are
believed to be primarily located in the spinothalamic tracts which
project via the reticular formation of the brainstem to the PVN.
Changes in blood pressure also affect CRH release. Blood pres-
J O H N S O N , KAMILARIS, CHROUSOS A N D GOLD
sure is regulated by receptors in the carotid sinus, the aortic
arch, major chest veins, and both atria. When blood pressure
increases, impulses originating from these receptors travel to the
nucleus of the tractus solitarius in the medulla and then to the
PVN, where CRH secretion is inhibited. Conversely, CRH se-
cretion is increased when blood pressure decreases. The latter
has been associated with a decrease in the number of impulses
reaching the PVN via the nucleus tractus solitarius (63).
Several neurotransmitter systems regulate PVN CRH release
(Fig. 1). Both NE and E stimulate CRH release. It appears that
the former stimulates CRH release via the a~-adrenergic receptor
(35). Acetylcholine and serotonin are also excitatory mediators
participating in both the circadian rhythm and stress-induced re-
lease of CRH, whereas gamma-aminobutyric acid (GABA), the
opioid peptide system, ACTH, and glucocorticoids are inhibitory
(35). Several products of the immune system such as several cy-
tokines, including Interleukin-1 (IL-I), Interleukin-2 (IL-2), In-
terleukin-6 (IL-6), or inflammatory mediators, such as platelet
activating factor (PAF) and tumor necrosis factor (TNF) appear
to stimulate secretion of hypothalamic CRH in vitro and in vivo
(19, 194, 216).
Behavioral effects. The distribution of CRH within and be-
yond the hypothalamus provides an anatomical context for the
observation that CRH can simultaneously activate and coordinate
metabolic, circulatory and behavioral responses during adaptive
situations (59, 64, 202). CRH injected directly into the cerebro-
ventricular system produces a number of effects that are remi-
niscent of the stress response (28,29). These include neuronal
activation, electroencephalographic arousal, and pronounced gen-
eral behavioral activation. Behavioral changes are dependent on
the situation and dose (102). For example, when CRH is injected
ICV in rats, it produces dose-dependent locomotor activation in
familiar environments and the "'freeze" posture in foreign envi-
ronments (202). At low doses, CRH-induced activation is char-
acterized by increased locomotion, sniffing, grooming and rearing.
These changes are believed to be consistent with "'general be-
havioral arousal." High doses of CRH, on the other hand, pro-
duce bizarre behaviors, including repetitive locomotion, irritability,
or demonstrations of aggression (102). High doses of CRH ICV
have been shown to decrease sexual behaviors (191). Finally,
CRH decreascs food intake in the home cage and inhibits in-
creases in food intake produced by NE and insulin, implicating
CRH as a mediator of stress-related suppression of appetite or
food intake (132).
ACTH and Endorphins
Anatomical distribution. Proopiomelanocortin (POMC) is the
prohormone for ACTH (122). POMC is synthesized in the brain
(arcuate nucleus of the hypothalamus, zona incerta, lateral sep-
tum, nucleus accumbens, periventricular thalamus, periaqueduc-
tal gray, locus coeruleus, nucleus tractus solitarius, reticular
formation, stria terminalis and medial amygdala), pituitary gland,
gastrointestinal tract and reproductive organs, and is cleaved into
different biologically active peptides (79, 84, 106, 137, 176). In
the anterior pituitary, POMC is broken down into ACTH, a 39
amino-acid fragment, and 13-1ipotropin, a 92 amino-acid frag-
ment; in turn, 13-1ipoprotein is broken further into other smaller
active fragments, including [3-endorphin (Fig. 2). The particular
POMC fragments produced in a given tissue or cell type are be-
lieved to be specific and determined by local enzymes and pH.
ACTH is transported via the systemic circulation to the adre-
nal gland, where it stimulates synthesis and secretion of gluco-
corticoids, aldosterone and adrenal androgens. ACTH also has a
trophic or sensitizing effect on the adrenal cortex, enhancing the
M E C H A N I S M S OF STRESS
NH2
I I
ACTH (1-391 ~°LPH
I I I !
13-MSH 11-131 CLIP 118-391 I'-LPH 11-5111
I i
~-MSH 137-S8)
FIG. 2. Schematic representation of proopiomelanocortin (POMC), the
large molecular weight precursor of ACTH, 13-1ipotropic hormone (13-
LPH), and [3-endorphin. CLIP represents corticotropin-like intermediate
lobe peptide, et-MSH, 13-MSH, and a- and [3-melanocyte-stimulating
hormones, respectively.
response to subsequent stimulation. Thus, if an animal is ex-
posed to regular, fixed doses of ACTH, the glucocorticoid re-
sponse to the dose increases over time, primarily as a result of
adrenocortical hypertrophy. The same occurs during chronic
stress. Conversely, if ACTH secretion is decreased or elimi-
nated, the glucocorticoid response to ACTH is reduced, most
probably as a result of adrenal atrophy. Interestingly, ACTH
may also have neurotrophic effects. For example, ACTH can fa-
cilitate recovery after a sciatic nerve crush (51,63).
Receptors. The ACTH receptor follows a pattern of receptor
regulation and homeostasis similar to that observed in most en-
docrine systems. When ACTH concentrations are high, recep-
tors are desensitized and are downregulated or disappear.
Conversely, when ACTH concentrations are low, the number or
sensitivity of the receptors increases. Although the ACTH recep-
tor system appears to follow a normal pattern, the glucocorti-
coid response to ACTH does not. Rather, elevations in ACTH
result in elevations in glucocorticoid secretion. Thus it appears
that the glucocorticoid responsivity to ACTH may be regulated
at the postreceptor level (109).
Regulation. CRH is the most potent stimulator of ACTH/13-
endorphin secretion from the anterior pituitary corticotrophs.
ACTH response to stress, however, is partially regulated by
peptides other than CRH. These include arginine vasopressin
(AVP), oxytocin (OT), angiotensin II, vasoactive intestinal poly-
peptide (VIP), serotonin, and, in the rat, E and NE (8, 148,
157). The physiologic role of these peptides in the regulation of
ACTH secretion is still not clear. AVP secreted by parvocellular
regions of the PVN into the hypophyseal portal circulation stim-
ulates ACTH release synergistically with CRH (177). Glucocor-
ticoids inhibit stimulated ACTH secretion both in vivo and in
vitro (99). The inhibitory effects in vivo exerted at least at two
levels, via inhibition of the secretion of hypothalamic CRH and
direct suppression of ACTH release at the pituitary level (34).
Behavior. ACTH, along with vasopressin, is believed to en-
hance attention, motivation, learning and memory retention (50,5 i).
It appears that only a small part of the ACTH molecule, amino
acids 4-7 of the N terminal, is needed to produce these effects
(50). Besides these positive effects, ACTH also acts as an opi-
ate antagonist, and competes with opiate-binding sites in the
brain. Thus ACTH can counteract morphine analgesia and re-
verse catatonic posture (immobility). ACTH administered ICV
also appears to affect social behavior in the rat by reducing so-
cial interaction and decreasing aggression. Novel or stressful
stimuli induce grooming, which has been related to the endoge-
nous release of ACTH (69).
The behavioral response to ICV ACTH is characterized by
the "stretching yawning syndrome," in which rats display ex-
cessive grooming behavior interrupted by bouts of stretching. In
contrast to CRH, ACTH given ICV does not appear to increase
activity or exploration (58,89). When injected peripherally, ACTH
119
COOH reduces exploration in a novel environment without influencing
11-gl) locomotion (57). The increased activity produced by ACTH is
l~-Enclorphln 161-gl1 about 100 times less potent than the changes produced by CRH.
y-Endorphln (81-77 I
I
Enl(ephlllln 161-115)
Glucocorticoids
The adrenal gland consists of at least two anatomically and
chemically distinct structures: an inner medullary area contain-
ing catecholamine-producing chromaffin cells and an outer corti-
cal region in which glucocorticoids and other steroids are
synthesized. Glucocorticoids are released from the adrenal gland
into the general circulation. A high proportion, almost 95%, of
circulating cortisol circulates bound to an alpha globulin called
"transcortin" or "corticosteroid-binding globulin" (CBG). The
bound fraction of cortisol is considered physiologically inactive.
The small free-fraction of cortisol in plasma represents the ac-
tive fraction of the hormone which exerts negative feedback ef-
fects on CRH and ACTH release (190).
Receptors. Glucocorticoid receptors are present throughout
the brain, including in the CRH neurons of the hypothalamus
(62). The actions of glucocorticoids on the central nervous sys-
tem (CNS) are mediated by two separate receptor systems: glu-
cocorticoid receptors type I and type II (155,173). Type I
("corticosterone receptors") receptors are found mainly in the
neurons of the limbic structures, such as the hippocampus and
septum (120). These receptors play a role in modulating the re-
sponse to environmental and emotional stimuli, with consequent
changes in behavior and HPA axis activity. Type I receptors
have a high affinity for the primary glucocorticoid (cortisol/cor-
ticosterone), and are similar to "mineralocorticoid receptors" of
the kidney (155,173). In the limbic system, these receptors have
a high specificity for corticosterone as an agonist, whereas the
mineralocorticoid aldosterone appears to be a competitive antag-
onist. The Type I receptors that are found in the circumventricu-
lar organs function as mineralocorticoid receptors that respond
to aldosterone and act to regulate sodium homeostasis, cardio-
vascular control and salt appetite (173). With age, the hippo-
campus loses approximately 50 percent of its glucocorticoid type
I binding sites (172). ACTH appears to have atrophic effect on
the CNS and reverses age-related decreases in type I receptor
(156).
Type II glucocorticoid receptors are present at high concen-
trations in the hypothalamus, particularly in the CRH neurons.
Type II receptors also are found in the brain areas that contain
POMC, such as the hippocampus, lateral septum, amygdala, and
nucleus tractus solitarius (120). At these sites, it is likely that
the receptors participate in the behavioral, neuroendocrine and
autonomic responses to stress (173). During stress, the occu-
pancy of type I receptor changes only minimally, whereas that
of type II receptor changes considerably (155). Glucocorticoids
exert negative feedback to terminate ACTH release in response
to stress and have long-term effects on adaptive behaviors, pre-
sumably via the type II receptors. Type II receptors diminish
with age, but are not affected by ACTH per se (156, 171-173).
Reduction of type II receptors is associated with decreases of
the negative feedback action of glucocorticoids, which may re-
sult in a more persistent elevation of circulating plasma cortico-
steroid levels following stress (167, 169, 171-173). In addition,
persistent elevations of circulating glucocorticoids render the
neurons of the hippocampus vulnerable to toxic influences with
consequent degeneration and death of the cells (i 10, 169-173).
Behavior. Glucocorticoids have two types of action in the
CNS. The first is associated with perception and the coordina-
tion of the circadian patterns of food intake and sleep. The sec-
ond is a negative feedback effect on stress-activated neural
120
circuits and metabolic processes. Interestingly, the acute effects
of glucocorticoids are euphorogenic, whereas chronically ele-
vated glucocorticoids produce depression in a large number of
subjects (27).
Autonomic System
As previously mentioned, the two principal components of
the general adaptational response are the CRH and the locus
ceruleus-norepinephrine, (LC-NE)/autonomic (sympathetic) ner-
vous systems (71,72) (Fig. 3). The LC-NE/sympathetic systems
are located in the brainstem (136). Activation of the LC-NE
system leads to release of norepinephrine from a dense network
of neurons throughout the brain that results in arousal, vigilance
and increased anxiety. It has been generally accepted that the
sympathetic division of the autonomic system is primarily asso-
ciated with conferring an adaptive advantage during stressful sit-
uations via its effectors, the sympathetic nerves and the adrenal
medulla, located in the periphery. On the other hand, the para-
sympathetic division of the autonomic nervous system, which is
functionally linked to the sympathetic system, appears to pro-
duce effects antithetical to those of the sympathetic nervous sys-
tem. Thus its inhibition can produce effects analogous to those
of sympathetic activation.
Cannon (37) was the first to note that a variety of stressors
resulted in an increase in sympathetic nervous system activity
and adrenal medulla output. During stress, E and NE are re-
leased into the general circulation and the activity of enzymes
that regulate catecholamines biosynthesis is stimulated. Today,
it is generally accepted that the general sympathetic and sym-
pathomedullary systems are critical elements in the integrated
physiological response of an organism to a variety of stressors
(8, 111, 118, 124). Central regulation of this response involves
components of the central stress system in the cerebral cortex,
limbic system, hypothalamus, and brainstem (60).
Acute stress results in secretion of E and NE from the adre-
nal medulla and release of NE from the sympathetic nerve ter-
minals (205). In contrast, chronic intermittent stress is associated
with changes in the adrenal medulla, including increased activ-
ity of enzymes involved in catecholamine biosynthesis, increased
rates of catecholamine synthesis and elevated tissue concentra-
tions of catecholamines (108). Chronic intermittent stressors ini-
tially appear to affect catecholamine release during subsequent
exposures, as a function of the familiarity of the stressor (101).
Thus exposure to homotypic (familiar) stressors in a chronic in-
termittent fashion results in a reduced sympathetic, sympath-
omedullary response with time. In contrast, following chronic
intermittent stress, exposure to an acute heterotypic (novel)
stressor results in an enhanced sympathetic, sympathomedullary
response (119,197).
There is growing body of studies that demonstrate that ani-
mals subjected to inescapable, uncontrollable electric shocks
show subsequent deficits in learning to terminate the noxious
stimulus even when it is escapable. This phenomenon has been
termed "learned helplessness," suggesting that the inability of
the individual to control or terminate the stressor results from
the initial learning of inescapability (181, 182, 213, 214). Ex-
perimentally induced behavioral deficits of this type have been
seen as a model of depression. Such a "learning deficit" was
considered analogous to some of the mood/cognitive distur-
bances observed in patients with depression, who frequently re-
port feelings of helplessness or powerlessness to cope with
stress. The weight of the available evidence suggests one mech-
anism underlying the behavioral deficits observed in animals ex-
posed to inescapable stress is a depletion of norepinephrine
JOHNSON, KAMILARIS, CHROUSOS AND GOLD
NE
\\\ ii ss
\ I
(~ituitary~ < \ ~ " E/NE
ACTH/
/' \\1IW
\ G,oc/o
iooi,s
Adrenal
FIG. 3. Schematic diagram of the functional interrelations between cor-
ticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine
(LC-NE) systems. These systems are the principal central biologic effec-
tors of the generalized stress response. In the periphery, both systems
act through glucocorticoids secreted from the adrenal cortex and the cat-
echolamines, epinephrine and norepinephrine (E, NE) from the sympa-
thetic and sympathomedullary systems (SS). Glucocorticoids are thought
to restrain both systems of the stress response, in order to prevent the
consequences of prolonged or excessive activation. (Solid lines represent
stimulatory effects; broken lines represent inhibitory effects.)
and/or a decrease in tyrosine hydroxylase activity (213,214).
The stress system also interacts with other CNS elements that
play a role in information processing, action initiation, as well
as setting the emotional tone. The mesocortical dopamine sys-
tem which innervates the prefrontal cortex, a brain region be-
lieved to be involved in anticipatory phenomena and cognitive
function, is activated by the LC-NE/sympathetic systems during
stress. In addition, the mesolimbic dopamine system, a region
closely linked to the nucleus accumbens, which has been impli-
cated in motivational/reinforcement/reward phenomena, is also
stimulated by the LC-NE/sympathetic systems during stress (48,
49, 136, 164). Noradrenergic neurons which originate in the
brainstem LC-NE/sympathetic system activate the amygdala/hip-
pocampus complex during stress (75).
Finally, the LC-NE/sympathetic systems seem to respond
similarly to the CRH system to many of the same neurochemi-
cal modulators. Serotonin and acetylcholine appear to be excita-
tory to the sympathetic system (5, 9, 12, 36, 61, 80), while the
gabaergic (9,61) and the opioid peptidergic (9, 23, 34, 80) neu-
rotransmissions act to inhibit the LC-NE/sympathetic systems. In
addition, the LC-NE/sympathetic systems seem to respond to
autoregulation by an alpha-2 adrenergic-mediated inhibition.
CONSEQUENCESOF STRESSON "'WELL-BEING":
THE INTERACTIONWITH OTHERPHYSIOLOGICSYSTEMS
The systems responsible for reproduction, growth and immu-
nity are directly linked to the stress system, and each is pro-
M E C H A N I S M S OF STRESS
foundly influenced by the effectors of the stress response. Chronic
stress can have physiological and behavioral consequences which
affect the well-being of an individual. These include accelerated
aging, reproductive suppression, retardation of growth, and im-
munosuppression. In addition, some common psychiatric disor-
ders, such as depression, panic anxiety and anorexia nervosa,
may represent dysregulation of the systems responding to stress.
Stress and Aging
There is general support for the notion that chronic stress can
accelerate aging (145) and that an aged animal has impaired
ability to terminate the stress response (171). It has been sug-
gested that cortisol hypersecretion in aged animals is due to de-
generative changes within the aging brain and loss of sensitivity
to glucocorticoid-mediated feedback inhibition. These effects are
seen specifically in the hippocampal region of the limbic sys-
tem, which has been associated with inhibition of the HPA axis
(173). With age, the hippocampus loses approximately 50 per-
cent of type I ("mineralocorticoid receptors") binding sites, as
well as some of the type II ("glucocorticoid receptors") sites
(172,173). In addition, the aged hippocampus demonstrates loss
of neurons (174). It appears that cumulative exposure to in-
creased glucocorticoid concentrations over the lifespan might
mediate hippocampal neuron death (110). Chronic stress or
pharmacologic doses of glucocorticoid treatment accelerate this
process (170, 173, 174). This effect appears to be specific for
the hippocampus, since other areas of the brain are spared (170).
Some of the damaging effects of glucocorticoids appear to be
mediated by type II glucocorticoid receptors. Hence, RU 486, a
type II receptor antagonist, attenuates these toxic effects of glu-
cocorticoids on the hippocampus (173).
Early neonatal experience may play a role in shaping indi-
vidual patterns of stress susceptibility in later life. Meany et al.
(125,126) have demonstrated that neonatal handling of rats in-
creases hippocampal glucocordcoid receptor levels. This is con-
cordant with their ability to shut off the pituitary-adrenal response
to stress. One could postulate that this enhanced capability to
terminate the secretion of adrenocortical stress hormones may
attenuate the glucocorticoid-dependent degenerative changes in
regions of the brain that participate in the restraint of the stress
response, particularly the hippocampus (174).
Suppression of Reproductive Function
The state of threatened homeostasis produced by physical or
emotional stress has long been recognized as a profound disrup-
tive factor in reproductive function. Females under stress may
demonstrate delayed puberty, lack of behavioral receptivity,
failure of ovulation or embryo implantation, spontaneous abor-
tion, or increased infant mortality (4, 10, 30, 117). Males may
exhibit suppression of testosterone secretion, spermatogenesis
and libido (2, 44, 152, 173). The severe suppression of repro-
duction during stress appears to be caused by several hormones
secreted during stress (such as CRH, ACTH, beta-endorphin and
glucocorticoids) on hypothalamic-pituitary-gonadal (HPG) axis
function (54, 81, 158, 161, 191, 211). Although the mecha-
nism(s) of these effects on reproductive function are not fully
elucidated, possible sites involved include: 1) a centrally medi-
ated inhibition of gonadotropin-releasing hormone (GnRH) re-
lease by CRH, opioids and glucocorticoids (158,161); 2) a
glucocorticoid-mediated decrease in pituitary responsiveness to
GnRH, resulting in decreased luteinizing hormone (LH) secre-
tion (81); 3) direct gonadal effects of glucocorticoids with sub-
sequent alterations in sex steroid output (13,39); and 4)
121
/
/;G}
/
/
/
ACTH / LH,FSH
nal ~~'Gonad
Target
Tissues
FIG. 4. Schematic representation of the functional interrelations between
the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-go-
nadal (HPG) axes. CRH activates the pituitary-adrenal axis and GnRH
the pituitary-gonadal axis, respectively. The activity of the GnRH-
secreting neurons during stress is inhibited by CRH directly or via hypo-
thalamic (arcuate nucleus) [3-endorphin(~-EP). Glucocorticoids suppress
the activity of the reproductive axis at all levels, including the hypothal-
amus, pituitary, gonads and target tissues of sex steroids. (Solid lines
represent stimulatory effects; broken lines represent inhibitory effects.)
glucocorticoid-induced sex steroid target tissue resistance to go-
nadal sex steroid (153) (Fig. 4).
Stress-induced decreases in circulating LH and sex steroid
levels have been observed in both males and female rats and
monkeys (24, 55, 139, 140). Abbott (1) demonstrated that, in
marmosets, socially mediated suppression of reproduction is as-
sociated with a significant reduction in LH release, resulting in
decreased sexual behaviors in males and lack of behavioral re-
ceptiveness and complete ovarian inactivity in females. Simi-
larly, O'Byme (139) showed that a summation of the stressful
effects of aggressive encounters and physical restraint produced
a suppression of LH secretion during estradiol-induced LH surges
in female marmosets. Although the site of action of socially in-
duced inhibition of LH release was not addressed in this study,
the fact that exogenous GnRH administration reversed the LH-
decrease in these animals supports the hypothesis that a centrally
mediated inhibition of GnRH secretion by hormones secreted
during stress could be related with the decrease of LH secretion
(1, 139, 140).
Previous studies have shown that disruptive effects of stress
on reproductive function in female animals and women may be
dependent on decreased gonadotropin secretion induced by ele-
vated endogenous CRH and opioid levels (14, 66, 68, 138, 146,
161). From these studies, it appears that the most probable
mechanism for reproductive inhibition involves CRH released
during stress and acting within the brain to inhibit gonadotropin
122
secretion, directly and/or indirectly through opioids (13-endor-
phin) (Fig. 3). This hypothesis is supported by several animal
studies in which ICV administration of either CRH neutralizing
antibodies or a specific CRH antagonist prevented CRH-induced
suppression of the HPG axis (146). Recent observations in the
rat have shown that the inhibitory effect of CRH on LH secre-
tion is blocked by anti-13-endorphin serum and by a 13-endorphin
antagonist, Blockage of [3-endorphin m and e receptors and
dynorphin k-receptors reverses footshock-induced decreases in
plasma LH levels, suggesting that multiple endogenous opiate
systems participate in stress-induced inhibition of reproduction
(146). The existence of a putative CRH-opioid interaction is
supported by the ability of nalaxone to reverse the CRH-induced
decrease in plasma LH levels in monkeys (68). Studies in amen-
orrheic anorexic patients showed that decreases in gonadotropin
secretion were associated with increased CRH and [3-endorphin
concentrations in the CSF (71, 86, 97, 98).
Another mechanism by which activation of the HPA axis may
influence reproductive function during stress is by direct effect
of glucocorticoids at multiple levels of the HPG axis. Glucocor-
ticoids suppress GnRH and gonadotropin secretion at both the
hypothalamic and pituitary levels (11,96). At the gonadal level,
glucocorticoids have a direct inhibitory effect on testicular Ley-
dig cell function. Leydig cell sensitivity to LH and hCG is de-
creased by glucocorticoids, probably due to glucocorticoid-
induced reductions in testicular LH receptors (13,39). In cycling
females, glucocorticoid treatment decreased estradiol concentra-
tions and caused resistance of the uterus to estradiol. The latter
has been associated with decreased estradiol receptors in the
uterus (153). Stress cannot only influence the ability of the fe-
male to conceive, but also can adversely affect the fecundity of
each conception. In rodents, stress during pregnancy has been
shown to result in smaller litter sizes (149,150). In sheep, there
also is evidence that stress and hypercortisolism are associated
with increased embryo loss following implantation and may pre-
cipitate premature labor (16, 87, 114).
Growth Retardation
In humans, linear growth and final adult stature depend on
multiple factors. These include genetic constitution (154), nutri-
tion (I 15), systemic disease (32,78), hormones (90) and psycho-
social environment (151). A putative association between stressful
psychosocial environment and subsequent physical stature, intel-
lectual and behavioral development has been described (I 29,130).
Psychosocial dwarfism, known also as abuse dwarfism, is a
human condition thought to result from disruptions of social re-
lationships in the neonatal environment; believed to be of partic-
ular importance is the withdrawal of normal " c a r e " by the
caregiver, which may act as an emotional stressor (151). This
syndrome is characterized by three primary reversible impair-
ments: 1) delayed physical maturation, defined by both lower
than normal body weight and height and delayed onset of pu-
berty; 2) retardation of intellectual age, indicated by regressive
or bizarre behaviors and retarded psychomotor development; and
3) delayed social maturation and slow psychosexual development
(7,77).
Studies of the biochemical basis of growth abnormalities in
children with psychosocial dwarfism have indicated that a "func-
tional" growth hormone (GH) deficiency exists, which normal-
izes rapidly with improved psychosocial environment (76,77).
Fasting plasma GH levels and GH response to insulin-induced
hypoglycemia are abnormally low in these children (77), and
IGF-I levels are in the range characteristically found in hypopi-
tuitarism (46). Although abnormalities in thyroid and adrenal
JOHNSON, KAMILARIS, CHROUSOS AND GOLD
/I /\,, \
I I iI \\
I
~IV \\\
\
it,
\
I .<...I /
I
Adrenal ',. / ~ /
Somatomedm i
Targel
Tissues
FIG. 5. Diagrammatic outline of the putative functional interrelations
between the HPA axis and hypothalamic-pituitary-growth axis. Growth
hormone (GH) secretion is under dual hypothalamic control of growth
hormone-releasing hormone (GRH), which is stimulatory, and soma-
tostatin, which is inhibitory. The activity of GRH neurons during stress
appears to inhibited by CRH directly and/or via hypothalamic [3-endor-
phin (13-EP) and somatostatin. GH exerts peripheral growth-promoting
actions directly by stimulating peripheral somatomedin-C (IGF-I) pro-
duction. Somatomedin-C appears to participate in a negative feedback
regulation of GH secretion at both the pituitary and the hypothalamus.
During chronic stress or hypercortisolemic states, glucocorticoids appear
to suppress spontaneous secretion of GH at the pituitary level and prob-
ably at the hypothalamus. In addition, glucocorticoids induce major tis-
sue resistance to somatomedin-C and other growth factors. (Solid lines
represent stimulatory effects; broken lines represent inhibitory effects.)
axis function have been reported in a few studies, they are not
typical (106).
It is a commonly hypothesized view is that glucocorticoids
and/or opioids secreted in response to chronic stress inhibit pitu-
itary GH release at the pituitary level and decrease target tissue
sensitivity to growth hormone, somatomedin-C or other growth
factors (Fig. 5). The recent observation that the central adminis-
tration of CRH decreases GH secretion in rats suggests a possi-
ble role of endogenous CRH in the modulation of GH secretion
during stress (142,159). Studies of the possible mechanisms in-
volved in this effect suggest a central site of action, since spe-
cific CRH antagonist administration abolished the inhibitory
effect of a noxious stimuli on GH secretion (160). Additionally,
the available data suggests that release of 13-endorphin and/or
somatostatin by CRH may represent important mediators of this
effect (15,160).
Studies in laboratory animals and humans have shown that
disruption of the infant-caregiver relationship, as in maternal
deprivation, rejection, or abuse, contributes to marked physio-
logical and behavioral abnormalities in the offspring. For in-
stance, it may impair overall skeletal growth and the ease with
which social bonds are formed later in development (56,179).
The mechanism(s) that mediate the linkage between early care
M E C H A N I S M S O F STRESS
or emotional state and the physical and behavioral manifestations
during development are not clear.
In many species, physical contact and touch between young
animals and their caregivers appears to be necessary for normal
somatic growth (56,179). In humans, the etiology of psychoso-
cial growth retardation has been related to unsatisfactory moth-
er-infant relationships, often measured in terms of physical contact
(76,77). In nonhuman primates, when physical contact is re-
strained, even if visual, auditory and olfactory cues are main-
mined, the behavioral development of the animal remains abnormal
(82). Rat pups that are separated from their mother or placed
with an anesthetized dam demonstrate decreases in tissue omi-
thine decarboxylase activity and GH secretion and reduced tis-
sue sensitivity to exogenous GH (179,180). These deficiencies
could be reversed with tactile stimulation (179).
Alterations in bnmunocompetence During Stress
The principal effectors of the stress response exert multiple,
complex effects on the immunologic apparatus. Conversely,
many humeral components of the immune response exert effects
on the central and peripheral components of the generalized
stress response (25,212l (Fig. 6l. These interactions are suffi-
ciently complex, as well as dose- and context-dependent, that
no single statement can simply summarize these interactions, We
shall try, therefore, to summarize only a few principles that have
been generally established regarding alterations in immunocom-
petence during stress.
Among the effectors of the stress response, the hypothala-
mic-pituitary-adrenal axis seems to be the most influential. The
HPA axis can influence immunologic function through a variety
of mechanisms, including CRH-mediated actions on the release
of somatostatin, with subsequent inhibition of growth hormone,
CRH-mediated release of ACTH and beta-endorphin, and CRH-
mediated pituitary-adrenal activation (25, 210, 212). Perhaps the
best understood and most widely studied immunologic effects of
the HPA axis are those mediated by glucocorticoids (17,133).
At plasma levels generally achieved during either emotional or
physical stress, including the stress of physical injury or inflam-
mation, glucocorticoids generally exert immunosuppressive and
antiinflammatory effects (17, 33, 133). These include inhibition
of leukocyte traffic, interference with cell-mediated immunity,
and enhancement of suppressor T-cell function (22, 67, 85, 123,
131, 133, 134). Moreover, there is a systematic decrease in the
production of cytokines and interference with their functional ef-
fects, as well as the induction of lymphopenia, thymic involu-
tion, and loss of splenic and lymph node tissue mass (17, 123,
131 ). It should be noted that, in some instances, glucocorticoids
enhance certain components of the immune response, including
the function of specific differentiated clones of lymphocytes
(194).
The CRH neuron of the HPA axis has recently been shown
to participate in a negative feedback loop, producing pituitary-
adrenal activation and concomitant glucocorticoid-mediated im-
munosuppression in response to peripheral mediators of the
inflammatory response, such as IFN, IL-I, IL-2, and PAF. This
negative feedback loop is thought to appropriately restrain the
immune and inflammatory response so that it will not overshoot
in response to immune triggers (25, 133, 212). Interruption of
this feedback loop by the administration of glucocorticoid antag-
onists or an endogenous deficiency in the responsiveness of the
CRH neuron to a variety of immune mediators results in suscep-
tibility to inflammatory disease. Hence, Sternberg et al. have
shown that the susceptibility of the LEW/N rat to a variety of
inflammatory diseases reflects a deficient responsiveness of the
123
CRH
~~_
P~ituitar~y~ ? CYet~ikitnes]°
f
"',.k,,.j/ ~ammation
ACTH
GlucocorticoidsJ
Adrenal
FIG. 6. A putaiive bidirectional regulatory feedback loop exists between
the immune system and the CRH system. Cytokines and inflammatory
mediators stimulate the HPA axis primarily by causing secretion of
CRH. The HPA axis, in turn, inhibits the immune/inflammatory re-
sponse primarily via increases in glucocorticoid secretion. This gluco-
corticoid-mediated immunosuppression could prevent excessive
inflammatory/immune responses during acute stress. (Solid lines repre-
sent stimulatory effects; broken lines represent inhibitory effects.)
CRH neuron to a variety of stimuli, including cytokines (195,196).
Conversely, histocompatible F/344N rats are resistant to inflam-
matory disease because of a hyperresponsiveness of their CRH
neurons to inflammatory mediators, but show the susceptibility
of LEW/N rats to a variety of immunogenic stimuli if given
small doses of the glucocorticoid antagonist RU 486 (195,196).
CRH has been shown not only to be essential for the activa-
tion of the pituitary-adrenal axis, but also to possess a variety of
behavioral effects when given ICV. Specifically, the central ad-
ministration of CRH not only activates the pituitary-adrenal axis,
but also sets into motion a variety of other physiological and
behavioral responses that are adaptive during stressful situations.
These include activation of the sympathetic nervous system, en-
hancement of pathways mediating cautious avoidance and anxi-
ety, and inhibition of pathways subserving vegetative functions
such as feeding and reproduction. Although not yet definitively
demonstrated, the response of the CRH neuron to the humeral
mediators of immunity such as IL-I and PAF could not only
serve to restrain the immune response to prevent it from over-
shooting, but could also promote behavioral adaption of value
during the stress of injury (17, 19, 25, 133, 194, 212, 216). As
an example, IL-l-mediated CRH release, leading to cautious re-
straint and increased anxiety, could serve to protect an animal
from exposing itself to further injury during the stress of illness
of prior injury. Such a dual role of a central element such as the
CRH neuron would bring the discipline of neuroimmunology full
circle by showing that the CNS could respond to peripherally
mediated inflammatory signals by modulating both the immuno-
logic and behavioral response of the organ to increase the likeli-
hood of survival.
124
It has been suggested that patients with major depression
show immunosuppression as a consequence of the hypercortiso-
lism frequently associated with this disorder (33). However. the
data have been conflicting. Although we cannot definitively ac-
count for the discrepancies, they could reflect the fact that glu-
cocorticoids are not always immunosuppressive, but may enhance
certain components of the immune response (17,25). A second
possibility is that not all depressive syndromes are associated
with hypercortisolism (73,74). Indeed, the weight of available
data suggests that, while the hyperaroused state of melancholia
is frequently associated with hypercortisolism, the hyperphagia
and hypersomnia of certain "atypical" depressions may be as-
sociated with a subtle central adrenal insufficiency, and hence
enhancement of certain immunologic responses. In this regard,
our group has recently noted that the atypical depression often
associated with the chronic fatigue syndrome, hypothyroidism,
and seasonal affective disorder may be associated with a subtle
deficiency in the responsiveness of the CRH neuron in associa-
tion with subtle adrenal insufficiency.
In addition to the CRH system, the LC-NE system is thought
to be the other major effector of the generalized stress response.
CRH is itself thought to be a potent stimulus to the LC-NE sys-
tem, although many neurotransmitters participate in the regula-
tion and counterregulation of this important stress responsive
system. NE is thought to have a variety of effects on the immu-
nologic response, acting both as a blood-borne humeral media-
tor and locally (194). As an example, the spleen and lymph
nodes are replete with noradrenergic terminals and adrenergic
receptors that modulate the functional activity of these lymphoid
organs.
Psychiatric Disorders
It has been proposed that a critical factor in the pathophysi-
ology of several psychiatric syndromes, such as major depres-
sion, anorexia nervosa and panic anxiety, stems from an
abnormality in the counterregulation of the generalized stress re-
sponse, resulting in CRH and/or central catecholamine hyperse-
cretion (192). In particular, it has been hypothesized that
abnormalities in the positive regulation of or defects in counter-
regulation of the central components of the adrenocortical and
adrenergic system are responsible for these disorders (73,74).
The association between stress and depression stem from
several observations: 1) individuals who are depression-prone
have a higher than expected incidence of early noxious stress or
maternal deprivation; 2) depressive episodes are often associated
with major life changes (73,74); 3) acute stress-induced hor-
monal and behavioral changes closely resemble the symptom
complex of depression (71); and 4) hypercortisolism is a consis-
tent feature of the classic form of major depression, melancholia
(165).
The symptom complex of melancholia indicates that depres-
sion need not be a state of pathological inactivation or suppres-
sion, as the term depression implies, but rather a state of
pathological hyperarousal (73,74). Indeed, from a clinical per-
spective, one can construe melancholia as an organized state of
anxiety attached principally to the self, resulting in a profound
sense of worthlessness and hopelessness about the future, pros-
pects of the worthless self. This anxiety about self and the fu-
ture are associated with other signs of hyperarousal or activation
of the generalized stress response that include enhanced vigi-
lance, as well as inhibition of vegetative functions such as feed-
ing, growth, reproduction, and sleep (73,74). Our group has
advanced several lines of evidence suggesting that CRH may
play a role in the clinical and biochemical manifestations of
melancholia (40, 41, 70-74, 101L As an example, we have
JOHNSON, KAMILARIS, CHROUSOS AND GOLD
shown that the plasma ACTH responses to exogenous CRH are
blunted in melancholia and correlate negatively with the basal
glucocorticoid levels. These data indicate that the pituitary corti-
cotroph cell in major depression is appropriately restrained by
high circulating glucocorticoids, and that hypercortisolism in
major depression reflects a defect at or above the hypothalamus
resulting in the hypersecretion of endogenous CRH (73,74). We
also showed that a continuous infusion of CRH to volunteers re-
produces the pattern and magnitude of hypercortisolism seen in
major depression, while postdexamethasone cortisol levels in
patients with major depression correlate positively with CSF
CRH levels (73,74). Recently, we have advanced preliminary
data that, in CSF sampled continuously for 30 hours, the levels
of CRH measured hourly are consistently higher in depressed
patients compared to controls (101).
This evidence of activation of one of the principal effectors
of the stress response in major depression is also associated with
evidence that the other major effector of the stress response, the
LC-NE system, is also activated in melancholia. Hence, patients
with melancholia show elevated levels of NE in CSF and plasma.
while successful responses to antidepressant treatment, regard-
less of the class, is associated with a significant fall in the
plasma and CSF levels of the principal NE metabolite, MHPG
(70-74, 101L In addition, tricyclic antidepressants which are the
most effective agents in the treatment of melancholia reduce the
LC firing rate, while we have recently shown that chronic but
not acute imipramine treatment causes a significant decrease in
the expression of TH mRNA in the LC. Taken together, these
data suggest that the clinical and biochemical manifestations of
major depression represent an activation of the major effectors
of the generalized stress response that have escaped their usual
counterregulatory elements to become pathologically established
as a syndrome of sustained hyperarousal and organized anxiety.
The principal animal models of major depression support
such a conclusion. These include the model of inescapable shock
or learned helplessness, analogous to the clinical context in
which many major depressions develop, namely sustained help-
lessness or a burden of internal conflict or external stress that is
inescapable (181, 182, 213, 214). Investigators such as Weiss
have shown that inescapable shock produces a syndrome in the
rat that is very analogous to that of melancholia, consisting of
early moming awakening, anorexia, decreased libido and hypo-
thalamic hypogonadism, shortened REM latency, and a behav-
ioral phenotype compatible with the organism's being overwhelmed
by stress (213,214). This syndrome responds to the classic treat-
ments for melancholia, including tricyclic antidepressants and
electroconvulsant treatment. It appears that the severity of the
behavioral disturbances following inescapable shock correlate
positively with the LC firing rate.
Although there has been a general emphasis on the role of
the aminergic systems in stress and depression, there is a grow-
ing body of evidence that suggests that supersensitivity of cen-
tral muscarinic mechanisms may be involved in the path-
ophysiology of depressive disorders (52, 53, 91-93). Stress re-
sults in the rapid activation of the septohippocampal cholinergic
system characterized by an increase in high-affinity uptake of
choline and the release of acetylcholine (ACh). The latter has
been shown to simultaneously induce alterations in behavioral,
cardiovascular and neuroendocrine function characteristic of those
observed during stress (52, 53, 143, 144). Hence, it has been
hypothesized that stress-induced changes in affective, neuroen-
docrine, sleep and heart rate profiles may reflect a central mus-
carinic cholinergic component. In this regard, in vivo and in
vitro data suggest that the muscarinic cholinergic agonist arec-
oline stimulates the HPA axis and that this effect is mediated
mainly by the release of endogenous CRH (36). In addition, it
MECHANISMS OF STRESS
appears that the functional activity of ACh and the secretion o f
hypothalamic CRH are increased in affective disorders. The
physiological relevance o f a CRH-mediated cholinergic stimula-
tion o f the HPA axis is underlined by data showing the involve-
ment o f cholinergic neurotransmission in both the stress response
and the pathophysiology o f affective disorders (52, 53, I00,
116).
Our group has recently advanced data that some forms o f
major depression may not be associated with activation o f stress-
responsive neurotransmitter systems, but rather with their inacti-
vation. This subtype, termed atypical depression and characterized
by evidence o f pathological hypoarousal such as profound leth-
argy, hypersomnia, and hyperphagia, occurs across the bound-
aries o f medical illnesses such as Cushing's disease, chronic
fatigue syndrome, hypothyroidism, and seasonal affective disor-
der (73,74). We have advanced several lines o f evidence that
these disorders are associated with a functional decrease in the
responsiveness o f the CRH neuron in these disorders stemming
from a variety of pathophysiological mechanisms. In Cushing's
disease, we postulate that the long-standing peripherally medi-
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