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Neuroscienceand BiobehavioralReviews, Vol. 16, pp. 115-130, 1992 0149-7634/92 $5.00 + .

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Printed in the USA. All rights reserved. Copyright © 1992 Pergamon Press Ltd.

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

TABLE 1 TABLE 2
THE CONCEPT OF HOMEOSTASIS HISTORY OF THE CONCEPT OF STRESS

Disturbing Harmony Counteracting Empedocles first written reference to homeostasis.


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

Glucocorico //
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 Adrenal
the generalized stress response could produce secondary changes
that interfere with adaptation, rather than promote it (181, 182, FIG. 1. Schematic representation of the putative regulation of the hypo-
2 1 3 , 2 1 4 ) . An analogy to this situation of an unrestrained or ex- thalamic-pituitary-adrenal (HPA) axis. The corticotropin-releasing hor-
cessive stress response is that of the spectrum of autoimmune mone (CRH) system is the principal central biologic effector which
diseases that occur as a consequence of excessive stimulation of facilitates a characteristic behavioral and peripheral response to stress.
the immune response or its escape from its usual counterregula- CRH stimulates secretion of both hypothalamic and pituitary POMC
tory elements (194-196). 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
Homeostasis and the Components of the Stress Response loops. (Solid lines represent stimulatory effects; broken lines represent
inhibitory effects.) The latter include an ultrashort CRH-mediated loop,
The HPA axis and the sympathetic system are important reg-
a short hypothalamic POMC gene-derived peptide loop, including both
ulators of an animal's homeostatic functions (205). Thus the or- ACTH and [3-endorphin, and a long glucocorticoid-mediated feedback
ganism's response to stress is composed of behavioral, endocrine, loop.
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- gogues from the hypothalamus (99, 133, 218) (Fig. 1).
ponents of the stress system restore homeostasis. Glucocorticoids exert many different effects, including effects
on cardiovascular function, metabolism, muscle function, behav-
MECHANISMS OF THE STRESS RESPONSE ior and the immune system (43). These effects can be grouped
Hypothalamic-Pituitary-Adrenal (HPA) A.ris into two categories defined as permissive and regulatory (88).
"Permissive" effects of glucocorticoids function to " p e r m i t "
The function of the HPA axis has been the subject of intense other hormones or factors to accomplish their function at a nor-
basic and clinical research which has attempted to understand mal level, and are observed primarily in the resting state and
why glucocorticoids are critical for life. The response to stress may span the resting and stress states. The permissive role of
is associated with increases in the levels of plasma glucocorti- glucocorticoids is crucial for maintenance of homeostasis at the
coids. The secretion of glucocorticoids from the adrenal cortex basal state (31, 103, 134, 157, 206). "Regulatory" effects of
is under the control of ACTH, which in turn is released from glucocorticoids are exerted only by stress-induced levels of these
the anterior lobe of the pituitary. ACTH secretion is regulated hormones. It has been hypothesized that the regulatory effects
by corticotropin-releasing hormone (CRH) and other secreta- of stress-related elevations of glucocorticoids may be necessary
118 J O H N S O N , KAMILARIS, CHROUSOS A N D GOLD

to prevent overreaction of the central stress, immune and other sure is regulated by receptors in the carotid sinus, the aortic
systems, which, if unchecked, lead to injury (133). arch, major chest veins, and both atria. When blood pressure
Several closed feedback mechanisms regulate the secretion of increases, impulses originating from these receptors travel to the
glucocorticoids (99, 133, 218) (Fig. 1). There is a major feed- nucleus of the tractus solitarius in the medulla and then to the
back loop between glucocorticoids and the hypothalamic-pitu- PVN, where CRH secretion is inhibited. Conversely, CRH se-
itary axis. Thus circulating glucocorticoids act on the pituitary cretion is increased when blood pressure decreases. The latter
directly to inhibit ACTH secretion, and on the hypothalamus to has been associated with a decrease in the number of impulses
suppress secretion of CRH (99). Additional feedback loops in- reaching the PVN via the nucleus tractus solitarius (63).
clude the inhibitory effects of ACTH, [3-endorphin ([3-EP) and Several neurotransmitter systems regulate PVN CRH release
CRH on the hypothalamic CRH neuron (34). These mechanisms (Fig. 1). Both NE and E stimulate CRH release. It appears that
enable the organism to maintain a stable blood level of gluco- the former stimulates CRH release via the a~-adrenergic receptor
corticoids at all times, while simultaneously providing an emer- (35). Acetylcholine and serotonin are also excitatory mediators
gency override, via the central nervous system (CNS), to respond participating in both the circadian rhythm and stress-induced re-
to stressors. lease of CRH, whereas gamma-aminobutyric acid (GABA), the
opioid peptide system, ACTH, and glucocorticoids are inhibitory
Corticotropin-Releasing Hormone ( CRH) (35). Several products of the immune system such as several cy-
tokines, including Interleukin-1 (IL-I), Interleukin-2 (IL-2), In-
It has long been recognized that the endocrine response to terleukin-6 (IL-6), or inflammatory mediators, such as platelet
stress is coordinated at the CNS. CRH is a 41 amino-acid pep- activating factor (PAF) and tumor necrosis factor (TNF) appear
tide secreted from the hypothalamus and has a putative role in to stimulate secretion of hypothalamic CRH in vitro and in vivo
regulating the normal response to stress. The chemical isolation (19, 194, 216).
and description of CRH by Vale provided an important missing Behavioral effects. The distribution of CRH within and be-
link in the system (207). The genes encoding the CRH molecule yond the hypothalamus provides an anatomical context for the
in the human, rat and sheep have been characterized (157, 178, observation that CRH can simultaneously activate and coordinate
189, 207). These genes have been highly conserved throughout metabolic, circulatory and behavioral responses during adaptive
evolution. In fact, the CRH peptides from humans and rats are situations (59, 64, 202). CRH injected directly into the cerebro-
identical in amino acid sequence (157,189). The existence of ventricular system produces a number of effects that are remi-
CRH has been known since the 1950's, but synthetic CRH only niscent of the stress response (28,29). These include neuronal
became available recently; the availability of synthetic CRH has activation, electroencephalographic arousal, and pronounced gen-
opened new experimental avenues. eral behavioral activation. Behavioral changes are dependent on
Anatomical distribution. CRH, localized by immunocyto- the situation and dose (102). For example, when CRH is injected
chemistry, is found in neuronal cell bodies in the paraventricular ICV in rats, it produces dose-dependent locomotor activation in
nucleus (PVN) (26,141). CRH neurons project to the median familiar environments and the "'freeze" posture in foreign envi-
eminence, where they terminate on the capillaries of the hy- ronments (202). At low doses, CRH-induced activation is char-
pophyseal portal vessels. These vessels function as a direct short acterized by increased locomotion, sniffing, grooming and rearing.
vascular pathway from the hypothalamus to the anterior pitu- These changes are believed to be consistent with "'general be-
itary. Thus CRH, which is released into the hypophyseal portal havioral arousal." High doses of CRH, on the other hand, pro-
system, is transported to the anterior pituitary, where it stimu- duce bizarre behaviors, including repetitive locomotion, irritability,
lates pituitary corticotrophs to both synthesize and secrete ACTH. or demonstrations of aggression (102). High doses of CRH ICV
A different set of PVN CRH neurons send projections to the have been shown to decrease sexual behaviors (191). Finally,
hindbrain, where they stimulate the electrical activity of their CRH decreascs food intake in the home cage and inhibits in-
target neurons in the arousal and sympathetic centers (208). creases in food intake produced by NE and insulin, implicating
There also are extrahypothalamic CRH neurons. Through im- CRH as a mediator of stress-related suppression of appetite or
munocytochemical, receptor studies and the detection of CRH food intake (132).
mRNA, CRH has been demonstrated in the brainstem, midbrain,
striatum, hippocampus, cerebral cortex, spinal cord, sympathetic
ACTH and Endorphins
ganglia and adrenal gland (47,199). The broad distribution of
CRH and its receptors in the CNS provides a substrate for the Anatomical distribution. Proopiomelanocortin (POMC) is the
wide-ranging behavioral effects of this peptide. prohormone for ACTH (122). POMC is synthesized in the brain
Receptors. The CRH receptor is highly concentrated in the (arcuate nucleus of the hypothalamus, zona incerta, lateral sep-
brain, anterior pituitary, adrenal medulla and sympathetic gan- tum, nucleus accumbens, periventricular thalamus, periaqueduc-
glia of the rat and several primates (45,209). CRH receptors in tal gray, locus coeruleus, nucleus tractus solitarius, reticular
pituitary corticotrophs appear to be sensitive to circulating levels formation, stria terminalis and medial amygdala), pituitary gland,
of glucocorticoids, as these receptors decrease shortly after adre- gastrointestinal tract and reproductive organs, and is cleaved into
nalectomy or during chronic stress (6,217). These conditions are different biologically active peptides (79, 84, 106, 137, 176). In
associated with increased hypothalamic CRH and vasopressin the anterior pituitary, POMC is broken down into ACTH, a 39
(AVP) secretion, and decreased responsiveness to physiologic amino-acid fragment, and 13-1ipotropin, a 92 amino-acid frag-
increases in plasma glucocorticoids, respectively. ment; in turn, 13-1ipoprotein is broken further into other smaller
Regulation. CRH secretion can be affected by stimuli such active fragments, including [3-endorphin (Fig. 2). The particular
as emotion, pain and changes in blood pressure. The PVN has POMC fragments produced in a given tissue or cell type are be-
connections with various components of the limbic system, im- lieved to be specific and determined by local enzymes and pH.
plicated in emotions, such as fear, and anger. Pain pathways are ACTH is transported via the systemic circulation to the adre-
believed to be primarily located in the spinothalamic tracts which nal gland, where it stimulates synthesis and secretion of gluco-
project via the reticular formation of the brainstem to the PVN. corticoids, aldosterone and adrenal androgens. ACTH also has a
Changes in blood pressure also affect CRH release. Blood pres- trophic or sensitizing effect on the adrenal cortex, enhancing the
M E C H A N I S M S OF STRESS 119

NH2
I I
COOH reduces exploration in a novel environment without influencing
ACTH (1-391 ~°LPH 11-gl) locomotion (57). The increased activity produced by ACTH is
I I I !
13-MSH 11-131 CLIP 118-391 I'-LPH 11-5111 l~-Enclorphln 161-gl1 about 100 times less potent than the changes produced by CRH.
I i
~-MSH 137-S8) y-Endorphln (81-77 I
I
Enl(ephlllln 161-115)
Glucocorticoids

The adrenal gland consists of at least two anatomically and


FIG. 2. Schematic representation of proopiomelanocortin (POMC), the chemically distinct structures: an inner medullary area contain-
large molecular weight precursor of ACTH, 13-1ipotropic hormone (13- ing catecholamine-producing chromaffin cells and an outer corti-
LPH), and [3-endorphin. CLIP represents corticotropin-like intermediate cal region in which glucocorticoids and other steroids are
lobe peptide, et-MSH, 13-MSH, and a- and [3-melanocyte-stimulating synthesized. Glucocorticoids are released from the adrenal gland
hormones, respectively. 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
response to subsequent stimulation. Thus, if an animal is ex- bound fraction of cortisol is considered physiologically inactive.
posed to regular, fixed doses of ACTH, the glucocorticoid re- The small free-fraction of cortisol in plasma represents the ac-
sponse to the dose increases over time, primarily as a result of tive fraction of the hormone which exerts negative feedback ef-
adrenocortical hypertrophy. The same occurs during chronic fects on CRH and ACTH release (190).
stress. Conversely, if ACTH secretion is decreased or elimi- Receptors. Glucocorticoid receptors are present throughout
nated, the glucocorticoid response to ACTH is reduced, most the brain, including in the CRH neurons of the hypothalamus
probably as a result of adrenal atrophy. Interestingly, ACTH (62). The actions of glucocorticoids on the central nervous sys-
may also have neurotrophic effects. For example, ACTH can fa- tem (CNS) are mediated by two separate receptor systems: glu-
cilitate recovery after a sciatic nerve crush (51,63). cocorticoid receptors type I and type II (155,173). Type I
Receptors. The ACTH receptor follows a pattern of receptor ("corticosterone receptors") receptors are found mainly in the
regulation and homeostasis similar to that observed in most en- neurons of the limbic structures, such as the hippocampus and
docrine systems. When ACTH concentrations are high, recep- septum (120). These receptors play a role in modulating the re-
tors are desensitized and are downregulated or disappear. sponse to environmental and emotional stimuli, with consequent
Conversely, when ACTH concentrations are low, the number or changes in behavior and HPA axis activity. Type I receptors
sensitivity of the receptors increases. Although the ACTH recep- have a high affinity for the primary glucocorticoid (cortisol/cor-
tor system appears to follow a normal pattern, the glucocorti- ticosterone), and are similar to "mineralocorticoid receptors" of
coid response to ACTH does not. Rather, elevations in ACTH the kidney (155,173). In the limbic system, these receptors have
result in elevations in glucocorticoid secretion. Thus it appears a high specificity for corticosterone as an agonist, whereas the
that the glucocorticoid responsivity to ACTH may be regulated mineralocorticoid aldosterone appears to be a competitive antag-
at the postreceptor level (109). onist. The Type I receptors that are found in the circumventricu-
Regulation. CRH is the most potent stimulator of ACTH/13- lar organs function as mineralocorticoid receptors that respond
endorphin secretion from the anterior pituitary corticotrophs. to aldosterone and act to regulate sodium homeostasis, cardio-
ACTH response to stress, however, is partially regulated by vascular control and salt appetite (173). With age, the hippo-
peptides other than CRH. These include arginine vasopressin campus loses approximately 50 percent of its glucocorticoid type
(AVP), oxytocin (OT), angiotensin II, vasoactive intestinal poly- I binding sites (172). ACTH appears to have atrophic effect on
peptide (VIP), serotonin, and, in the rat, E and NE (8, 148, the CNS and reverses age-related decreases in type I receptor
157). The physiologic role of these peptides in the regulation of (156).
ACTH secretion is still not clear. AVP secreted by parvocellular Type II glucocorticoid receptors are present at high concen-
regions of the PVN into the hypophyseal portal circulation stim- trations in the hypothalamus, particularly in the CRH neurons.
ulates ACTH release synergistically with CRH (177). Glucocor- Type II receptors also are found in the brain areas that contain
ticoids inhibit stimulated ACTH secretion both in vivo and in POMC, such as the hippocampus, lateral septum, amygdala, and
vitro (99). The inhibitory effects in vivo exerted at least at two nucleus tractus solitarius (120). At these sites, it is likely that
levels, via inhibition of the secretion of hypothalamic CRH and the receptors participate in the behavioral, neuroendocrine and
direct suppression of ACTH release at the pituitary level (34). autonomic responses to stress (173). During stress, the occu-
Behavior. ACTH, along with vasopressin, is believed to en- pancy of type I receptor changes only minimally, whereas that
hance attention, motivation, learning and memory retention (50,5 i). of type II receptor changes considerably (155). Glucocorticoids
It appears that only a small part of the ACTH molecule, amino exert negative feedback to terminate ACTH release in response
acids 4-7 of the N terminal, is needed to produce these effects to stress and have long-term effects on adaptive behaviors, pre-
(50). Besides these positive effects, ACTH also acts as an opi- sumably via the type II receptors. Type II receptors diminish
ate antagonist, and competes with opiate-binding sites in the with age, but are not affected by ACTH per se (156, 171-173).
brain. Thus ACTH can counteract morphine analgesia and re- Reduction of type II receptors is associated with decreases of
verse catatonic posture (immobility). ACTH administered ICV the negative feedback action of glucocorticoids, which may re-
also appears to affect social behavior in the rat by reducing so- sult in a more persistent elevation of circulating plasma cortico-
cial interaction and decreasing aggression. Novel or stressful steroid levels following stress (167, 169, 171-173). In addition,
stimuli induce grooming, which has been related to the endoge- persistent elevations of circulating glucocorticoids render the
nous release of ACTH (69). neurons of the hippocampus vulnerable to toxic influences with
The behavioral response to ICV ACTH is characterized by consequent degeneration and death of the cells (i 10, 169-173).
the "stretching yawning syndrome," in which rats display ex- Behavior. Glucocorticoids have two types of action in the
cessive grooming behavior interrupted by bouts of stretching. In CNS. The first is associated with perception and the coordina-
contrast to CRH, ACTH given ICV does not appear to increase tion of the circadian patterns of food intake and sleep. The sec-
activity or exploration (58,89). When injected peripherally, ACTH ond is a negative feedback effect on stress-activated neural
120 JOHNSON, KAMILARIS, CHROUSOS AND GOLD

circuits and metabolic processes. Interestingly, the acute effects NE


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-
\\\ ii ss

vous systems (71,72) (Fig. 3). The LC-NE/sympathetic systems


are located in the brainstem (136). Activation of the LC-NE
\ I
system leads to release of norepinephrine from a dense network
of neurons throughout the brain that results in arousal, vigilance
(~ituitary~ < \ ~ " E/NE
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
ACTH/
/' \\1IW
medulla, located in the periphery. On the other hand, the para-
sympathetic division of the autonomic nervous system, which is \ G,oc/o
iooi,s
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 Adrenal
and adrenal medulla output. During stress, E and NE are re-
leased into the general circulation and the activity of enzymes
FIG. 3. Schematic diagram of the functional interrelations between cor-
that regulate catecholamines biosynthesis is stimulated. Today, ticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine
it is generally accepted that the general sympathetic and sym- (LC-NE) systems. These systems are the principal central biologic effec-
pathomedullary systems are critical elements in the integrated tors of the generalized stress response. In the periphery, both systems
physiological response of an organism to a variety of stressors act through glucocorticoids secreted from the adrenal cortex and the cat-
(8, 111, 118, 124). Central regulation of this response involves echolamines, epinephrine and norepinephrine (E, NE) from the sympa-
components of the central stress system in the cerebral cortex, thetic and sympathomedullary systems (SS). Glucocorticoids are thought
limbic system, hypothalamus, and brainstem (60). to restrain both systems of the stress response, in order to prevent the
Acute stress results in secretion of E and NE from the adre- consequences of prolonged or excessive activation. (Solid lines represent
nal medulla and release of NE from the sympathetic nerve ter- stimulatory effects; broken lines represent inhibitory effects.)
minals (205). In contrast, chronic intermittent stress is associated
with changes in the adrenal medulla, including increased activ- and/or a decrease in tyrosine hydroxylase activity (213,214).
ity of enzymes involved in catecholamine biosynthesis, increased The stress system also interacts with other CNS elements that
rates of catecholamine synthesis and elevated tissue concentra- play a role in information processing, action initiation, as well
tions of catecholamines (108). Chronic intermittent stressors ini- as setting the emotional tone. The mesocortical dopamine sys-
tially appear to affect catecholamine release during subsequent tem which innervates the prefrontal cortex, a brain region be-
exposures, as a function of the familiarity of the stressor (101). lieved to be involved in anticipatory phenomena and cognitive
Thus exposure to homotypic (familiar) stressors in a chronic in- function, is activated by the LC-NE/sympathetic systems during
termittent fashion results in a reduced sympathetic, sympath- stress. In addition, the mesolimbic dopamine system, a region
omedullary response with time. In contrast, following chronic closely linked to the nucleus accumbens, which has been impli-
intermittent stress, exposure to an acute heterotypic (novel) cated in motivational/reinforcement/reward phenomena, is also
stressor results in an enhanced sympathetic, sympathomedullary stimulated by the LC-NE/sympathetic systems during stress (48,
response (119,197). 49, 136, 164). Noradrenergic neurons which originate in the
There is growing body of studies that demonstrate that ani- brainstem LC-NE/sympathetic system activate the amygdala/hip-
mals subjected to inescapable, uncontrollable electric shocks pocampus complex during stress (75).
show subsequent deficits in learning to terminate the noxious Finally, the LC-NE/sympathetic systems seem to respond
stimulus even when it is escapable. This phenomenon has been similarly to the CRH system to many of the same neurochemi-
termed "learned helplessness," suggesting that the inability of cal modulators. Serotonin and acetylcholine appear to be excita-
the individual to control or terminate the stressor results from tory to the sympathetic system (5, 9, 12, 36, 61, 80), while the
the initial learning of inescapability (181, 182, 213, 214). Ex- gabaergic (9,61) and the opioid peptidergic (9, 23, 34, 80) neu-
perimentally induced behavioral deficits of this type have been rotransmissions act to inhibit the LC-NE/sympathetic systems. In
seen as a model of depression. Such a "learning deficit" was addition, the LC-NE/sympathetic systems seem to respond to
considered analogous to some of the mood/cognitive distur- autoregulation by an alpha-2 adrenergic-mediated inhibition.
bances observed in patients with depression, who frequently re-
port feelings of helplessness or powerlessness to cope with CONSEQUENCESOF STRESSON "'WELL-BEING":
stress. The weight of the available evidence suggests one mech- THE INTERACTIONWITH OTHERPHYSIOLOGICSYSTEMS
anism underlying the behavioral deficits observed in animals ex- The systems responsible for reproduction, growth and immu-
posed to inescapable stress is a depletion of norepinephrine nity are directly linked to the stress system, and each is pro-
M E C H A N I S M S OF STRESS 121

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- /

/;G}
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 ACTH / LH,FSH
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- nal ~~'Gonad
creased glucocorticoid concentrations over the lifespan might
mediate hippocampal neuron death (110). Chronic stress or
pharmacologic doses of glucocorticoid treatment accelerate this Target
process (170, 173, 174). This effect appears to be specific for Tissues
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 FIG. 4. Schematic representation of the functional interrelations between
the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-go-
type II receptor antagonist, attenuates these toxic effects of glu- nadal (HPG) axes. CRH activates the pituitary-adrenal axis and GnRH
cocorticoids on the hippocampus (173). the pituitary-gonadal axis, respectively. The activity of the GnRH-
Early neonatal experience may play a role in shaping indi- secreting neurons during stress is inhibited by CRH directly or via hypo-
vidual patterns of stress susceptibility in later life. Meany et al. thalamic (arcuate nucleus) [3-endorphin(~-EP). Glucocorticoids suppress
(125,126) have demonstrated that neonatal handling of rats in- the activity of the reproductive axis at all levels, including the hypothal-
creases hippocampal glucocordcoid receptor levels. This is con- amus, pituitary, gonads and target tissues of sex steroids. (Solid lines
cordant with their ability to shut off the pituitary-adrenal response represent stimulatory effects; broken lines represent inhibitory effects.)
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 glucocorticoid-induced sex steroid target tissue resistance to go-
regions of the brain that participate in the restraint of the stress nadal sex steroid (153) (Fig. 4).
response, particularly the hippocampus (174). Stress-induced decreases in circulating LH and sex steroid
levels have been observed in both males and female rats and
Suppression of Reproductive Function monkeys (24, 55, 139, 140). Abbott (1) demonstrated that, in
marmosets, socially mediated suppression of reproduction is as-
The state of threatened homeostasis produced by physical or sociated with a significant reduction in LH release, resulting in
emotional stress has long been recognized as a profound disrup- decreased sexual behaviors in males and lack of behavioral re-
tive factor in reproductive function. Females under stress may ceptiveness and complete ovarian inactivity in females. Simi-
demonstrate delayed puberty, lack of behavioral receptivity, larly, O'Byme (139) showed that a summation of the stressful
failure of ovulation or embryo implantation, spontaneous abor- effects of aggressive encounters and physical restraint produced
tion, or increased infant mortality (4, 10, 30, 117). Males may a suppression of LH secretion during estradiol-induced LH surges
exhibit suppression of testosterone secretion, spermatogenesis in female marmosets. Although the site of action of socially in-
and libido (2, 44, 152, 173). The severe suppression of repro- duced inhibition of LH release was not addressed in this study,
duction during stress appears to be caused by several hormones the fact that exogenous GnRH administration reversed the LH-
secreted during stress (such as CRH, ACTH, beta-endorphin and decrease in these animals supports the hypothesis that a centrally
glucocorticoids) on hypothalamic-pituitary-gonadal (HPG) axis mediated inhibition of GnRH secretion by hormones secreted
function (54, 81, 158, 161, 191, 211). Although the mecha- during stress could be related with the decrease of LH secretion
nism(s) of these effects on reproductive function are not fully (1, 139, 140).
elucidated, possible sites involved include: 1) a centrally medi- Previous studies have shown that disruptive effects of stress
ated inhibition of gonadotropin-releasing hormone (GnRH) re- on reproductive function in female animals and women may be
lease by CRH, opioids and glucocorticoids (158,161); 2) a dependent on decreased gonadotropin secretion induced by ele-
glucocorticoid-mediated decrease in pituitary responsiveness to vated endogenous CRH and opioid levels (14, 66, 68, 138, 146,
GnRH, resulting in decreased luteinizing hormone (LH) secre- 161). From these studies, it appears that the most probable
tion (81); 3) direct gonadal effects of glucocorticoids with sub- mechanism for reproductive inhibition involves CRH released
sequent alterations in sex steroid output (13,39); and 4) during stress and acting within the brain to inhibit gonadotropin
122 JOHNSON, KAMILARIS, CHROUSOS AND GOLD

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 /I /\,, \
rat have shown that the inhibitory effect of CRH on LH secre- I I iI \\
tion is blocked by anti-13-endorphin serum and by a 13-endorphin
I
~IV \\\
\
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
it,
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
I .<...I /
I
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 Adrenal ',. / ~ /
hypothalamic and pituitary levels (11,96). At the gonadal level, Somatomedm i
glucocorticoids have a direct inhibitory effect on testicular Ley-
dig cell function. Leydig cell sensitivity to LH and hCG is de- Targel
creased by glucocorticoids, probably due to glucocorticoid- Tissues
induced reductions in testicular LH receptors (13,39). In cycling
females, glucocorticoid treatment decreased estradiol concentra- FIG. 5. Diagrammatic outline of the putative functional interrelations
tions and caused resistance of the uterus to estradiol. The latter between the HPA axis and hypothalamic-pituitary-growth axis. Growth
has been associated with decreased estradiol receptors in the hormone (GH) secretion is under dual hypothalamic control of growth
uterus (153). Stress cannot only influence the ability of the fe- hormone-releasing hormone (GRH), which is stimulatory, and soma-
male to conceive, but also can adversely affect the fecundity of tostatin, which is inhibitory. The activity of GRH neurons during stress
each conception. In rodents, stress during pregnancy has been appears to inhibited by CRH directly and/or via hypothalamic [3-endor-
shown to result in smaller litter sizes (149,150). In sheep, there phin (13-EP) and somatostatin. GH exerts peripheral growth-promoting
also is evidence that stress and hypercortisolism are associated actions directly by stimulating peripheral somatomedin-C (IGF-I) pro-
duction. Somatomedin-C appears to participate in a negative feedback
with increased embryo loss following implantation and may pre-
regulation of GH secretion at both the pituitary and the hypothalamus.
cipitate premature labor (16, 87, 114). During chronic stress or hypercortisolemic states, glucocorticoids appear
to suppress spontaneous secretion of GH at the pituitary level and prob-
Growth Retardation ably at the hypothalamus. In addition, glucocorticoids induce major tis-
sue resistance to somatomedin-C and other growth factors. (Solid lines
In humans, linear growth and final adult stature depend on represent stimulatory effects; broken lines represent inhibitory effects.)
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 axis function have been reported in a few studies, they are not
psychosocial environment and subsequent physical stature, intel- typical (106).
lectual and behavioral development has been described (I 29,130). It is a commonly hypothesized view is that glucocorticoids
Psychosocial dwarfism, known also as abuse dwarfism, is a and/or opioids secreted in response to chronic stress inhibit pitu-
human condition thought to result from disruptions of social re- itary GH release at the pituitary level and decrease target tissue
lationships in the neonatal environment; believed to be of partic- sensitivity to growth hormone, somatomedin-C or other growth
ular importance is the withdrawal of normal " c a r e " by the factors (Fig. 5). The recent observation that the central adminis-
caregiver, which may act as an emotional stressor (151). This tration of CRH decreases GH secretion in rats suggests a possi-
syndrome is characterized by three primary reversible impair- ble role of endogenous CRH in the modulation of GH secretion
ments: 1) delayed physical maturation, defined by both lower during stress (142,159). Studies of the possible mechanisms in-
than normal body weight and height and delayed onset of pu- volved in this effect suggest a central site of action, since spe-
berty; 2) retardation of intellectual age, indicated by regressive cific CRH antagonist administration abolished the inhibitory
or bizarre behaviors and retarded psychomotor development; and effect of a noxious stimuli on GH secretion (160). Additionally,
3) delayed social maturation and slow psychosexual development the available data suggests that release of 13-endorphin and/or
(7,77). somatostatin by CRH may represent important mediators of this
Studies of the biochemical basis of growth abnormalities in effect (15,160).
children with psychosocial dwarfism have indicated that a "func- Studies in laboratory animals and humans have shown that
tional" growth hormone (GH) deficiency exists, which normal- disruption of the infant-caregiver relationship, as in maternal
izes rapidly with improved psychosocial environment (76,77). deprivation, rejection, or abuse, contributes to marked physio-
Fasting plasma GH levels and GH response to insulin-induced logical and behavioral abnormalities in the offspring. For in-
hypoglycemia are abnormally low in these children (77), and stance, it may impair overall skeletal growth and the ease with
IGF-I levels are in the range characteristically found in hypopi- which social bonds are formed later in development (56,179).
tuitarism (46). Although abnormalities in thyroid and adrenal The mechanism(s) that mediate the linkage between early care
M E C H A N I S M S O F STRESS 123

or emotional state and the physical and behavioral manifestations


during development are not clear.
In many species, physical contact and touch between young
CRH
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- ~~_
P~ituitar~y~ ? CYet~ikitnes]°
f
thine decarboxylase activity and GH secretion and reduced tis-
sue sensitivity to exogenous GH (179,180). These deficiencies
"',.k,,.j/ ~ammation
could be reversed with tactile stimulation (179).

Alterations in bnmunocompetence During Stress


ACTH
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-
GlucocorticoidsJ
ciently complex, as well as dose- and context-dependent, that
no single statement can simply summarize these interactions, We Adrenal
shall try, therefore, to summarize only a few principles that have
been generally established regarding alterations in immunocom- FIG. 6. A putaiive bidirectional regulatory feedback loop exists between
petence during stress. the immune system and the CRH system. Cytokines and inflammatory
Among the effectors of the stress response, the hypothala- mediators stimulate the HPA axis primarily by causing secretion of
mic-pituitary-adrenal axis seems to be the most influential. The CRH. The HPA axis, in turn, inhibits the immune/inflammatory re-
HPA axis can influence immunologic function through a variety sponse primarily via increases in glucocorticoid secretion. This gluco-
of mechanisms, including CRH-mediated actions on the release corticoid-mediated immunosuppression could prevent excessive
of somatostatin, with subsequent inhibition of growth hormone, inflammatory/immune responses during acute stress. (Solid lines repre-
sent stimulatory effects; broken lines represent inhibitory effects.)
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 CRH neuron to a variety of stimuli, including cytokines (195,196).
the HPA axis are those mediated by glucocorticoids (17,133). Conversely, histocompatible F/344N rats are resistant to inflam-
At plasma levels generally achieved during either emotional or matory disease because of a hyperresponsiveness of their CRH
physical stress, including the stress of physical injury or inflam- neurons to inflammatory mediators, but show the susceptibility
mation, glucocorticoids generally exert immunosuppressive and of LEW/N rats to a variety of immunogenic stimuli if given
antiinflammatory effects (17, 33, 133). These include inhibition small doses of the glucocorticoid antagonist RU 486 (195,196).
of leukocyte traffic, interference with cell-mediated immunity, CRH has been shown not only to be essential for the activa-
and enhancement of suppressor T-cell function (22, 67, 85, 123, tion of the pituitary-adrenal axis, but also to possess a variety of
131, 133, 134). Moreover, there is a systematic decrease in the behavioral effects when given ICV. Specifically, the central ad-
production of cytokines and interference with their functional ef- ministration of CRH not only activates the pituitary-adrenal axis,
fects, as well as the induction of lymphopenia, thymic involu- but also sets into motion a variety of other physiological and
tion, and loss of splenic and lymph node tissue mass (17, 123, behavioral responses that are adaptive during stressful situations.
131 ). It should be noted that, in some instances, glucocorticoids These include activation of the sympathetic nervous system, en-
enhance certain components of the immune response, including hancement of pathways mediating cautious avoidance and anxi-
the function of specific differentiated clones of lymphocytes ety, and inhibition of pathways subserving vegetative functions
(194). such as feeding and reproduction. Although not yet definitively
The CRH neuron of the HPA axis has recently been shown demonstrated, the response of the CRH neuron to the humeral
to participate in a negative feedback loop, producing pituitary- mediators of immunity such as IL-I and PAF could not only
adrenal activation and concomitant glucocorticoid-mediated im- serve to restrain the immune response to prevent it from over-
munosuppression in response to peripheral mediators of the shooting, but could also promote behavioral adaption of value
inflammatory response, such as IFN, IL-I, IL-2, and PAF. This during the stress of injury (17, 19, 25, 133, 194, 212, 216). As
negative feedback loop is thought to appropriately restrain the an example, IL-l-mediated CRH release, leading to cautious re-
immune and inflammatory response so that it will not overshoot straint and increased anxiety, could serve to protect an animal
in response to immune triggers (25, 133, 212). Interruption of from exposing itself to further injury during the stress of illness
this feedback loop by the administration of glucocorticoid antag- of prior injury. Such a dual role of a central element such as the
onists or an endogenous deficiency in the responsiveness of the CRH neuron would bring the discipline of neuroimmunology full
CRH neuron to a variety of immune mediators results in suscep- circle by showing that the CNS could respond to peripherally
tibility to inflammatory disease. Hence, Sternberg et al. have mediated inflammatory signals by modulating both the immuno-
shown that the susceptibility of the LEW/N rat to a variety of logic and behavioral response of the organ to increase the likeli-
inflammatory diseases reflects a deficient responsiveness of the hood of survival.
124 JOHNSON, KAMILARIS, CHROUSOS AND GOLD

It has been suggested that patients with major depression shown that the plasma ACTH responses to exogenous CRH are
show immunosuppression as a consequence of the hypercortiso- blunted in melancholia and correlate negatively with the basal
lism frequently associated with this disorder (33). However. the glucocorticoid levels. These data indicate that the pituitary corti-
data have been conflicting. Although we cannot definitively ac- cotroph cell in major depression is appropriately restrained by
count for the discrepancies, they could reflect the fact that glu- high circulating glucocorticoids, and that hypercortisolism in
cocorticoids are not always immunosuppressive, but may enhance major depression reflects a defect at or above the hypothalamus
certain components of the immune response (17,25). A second resulting in the hypersecretion of endogenous CRH (73,74). We
possibility is that not all depressive syndromes are associated also showed that a continuous infusion of CRH to volunteers re-
with hypercortisolism (73,74). Indeed, the weight of available produces the pattern and magnitude of hypercortisolism seen in
data suggests that, while the hyperaroused state of melancholia major depression, while postdexamethasone cortisol levels in
is frequently associated with hypercortisolism, the hyperphagia patients with major depression correlate positively with CSF
and hypersomnia of certain "atypical" depressions may be as- CRH levels (73,74). Recently, we have advanced preliminary
sociated with a subtle central adrenal insufficiency, and hence data that, in CSF sampled continuously for 30 hours, the levels
enhancement of certain immunologic responses. In this regard, of CRH measured hourly are consistently higher in depressed
our group has recently noted that the atypical depression often patients compared to controls (101).
associated with the chronic fatigue syndrome, hypothyroidism, This evidence of activation of one of the principal effectors
and seasonal affective disorder may be associated with a subtle of the stress response in major depression is also associated with
deficiency in the responsiveness of the CRH neuron in associa- evidence that the other major effector of the stress response, the
tion with subtle adrenal insufficiency. LC-NE system, is also activated in melancholia. Hence, patients
In addition to the CRH system, the LC-NE system is thought with melancholia show elevated levels of NE in CSF and plasma.
to be the other major effector of the generalized stress response. while successful responses to antidepressant treatment, regard-
CRH is itself thought to be a potent stimulus to the LC-NE sys- less of the class, is associated with a significant fall in the
tem, although many neurotransmitters participate in the regula- plasma and CSF levels of the principal NE metabolite, MHPG
tion and counterregulation of this important stress responsive (70-74, 101L In addition, tricyclic antidepressants which are the
system. NE is thought to have a variety of effects on the immu- most effective agents in the treatment of melancholia reduce the
nologic response, acting both as a blood-borne humeral media- LC firing rate, while we have recently shown that chronic but
tor and locally (194). As an example, the spleen and lymph not acute imipramine treatment causes a significant decrease in
nodes are replete with noradrenergic terminals and adrenergic the expression of TH mRNA in the LC. Taken together, these
receptors that modulate the functional activity of these lymphoid data suggest that the clinical and biochemical manifestations of
organs. major depression represent an activation of the major effectors
of the generalized stress response that have escaped their usual
Psychiatric Disorders counterregulatory elements to become pathologically established
as a syndrome of sustained hyperarousal and organized anxiety.
It has been proposed that a critical factor in the pathophysi- The principal animal models of major depression support
ology of several psychiatric syndromes, such as major depres- such a conclusion. These include the model of inescapable shock
sion, anorexia nervosa and panic anxiety, stems from an or learned helplessness, analogous to the clinical context in
abnormality in the counterregulation of the generalized stress re- which many major depressions develop, namely sustained help-
sponse, resulting in CRH and/or central catecholamine hyperse- lessness or a burden of internal conflict or external stress that is
cretion (192). In particular, it has been hypothesized that inescapable (181, 182, 213, 214). Investigators such as Weiss
abnormalities in the positive regulation of or defects in counter- have shown that inescapable shock produces a syndrome in the
regulation of the central components of the adrenocortical and rat that is very analogous to that of melancholia, consisting of
adrenergic system are responsible for these disorders (73,74). early moming awakening, anorexia, decreased libido and hypo-
The association between stress and depression stem from thalamic hypogonadism, shortened REM latency, and a behav-
several observations: 1) individuals who are depression-prone ioral phenotype compatible with the organism's being overwhelmed
have a higher than expected incidence of early noxious stress or by stress (213,214). This syndrome responds to the classic treat-
maternal deprivation; 2) depressive episodes are often associated ments for melancholia, including tricyclic antidepressants and
with major life changes (73,74); 3) acute stress-induced hor- electroconvulsant treatment. It appears that the severity of the
monal and behavioral changes closely resemble the symptom behavioral disturbances following inescapable shock correlate
complex of depression (71); and 4) hypercortisolism is a consis- positively with the LC firing rate.
tent feature of the classic form of major depression, melancholia Although there has been a general emphasis on the role of
(165). the aminergic systems in stress and depression, there is a grow-
The symptom complex of melancholia indicates that depres- ing body of evidence that suggests that supersensitivity of cen-
sion need not be a state of pathological inactivation or suppres- tral muscarinic mechanisms may be involved in the path-
sion, as the term depression implies, but rather a state of ophysiology of depressive disorders (52, 53, 91-93). Stress re-
pathological hyperarousal (73,74). Indeed, from a clinical per- sults in the rapid activation of the septohippocampal cholinergic
spective, one can construe melancholia as an organized state of system characterized by an increase in high-affinity uptake of
anxiety attached principally to the self, resulting in a profound choline and the release of acetylcholine (ACh). The latter has
sense of worthlessness and hopelessness about the future, pros- been shown to simultaneously induce alterations in behavioral,
pects of the worthless self. This anxiety about self and the fu- cardiovascular and neuroendocrine function characteristic of those
ture are associated with other signs of hyperarousal or activation observed during stress (52, 53, 143, 144). Hence, it has been
of the generalized stress response that include enhanced vigi- hypothesized that stress-induced changes in affective, neuroen-
lance, as well as inhibition of vegetative functions such as feed- docrine, sleep and heart rate profiles may reflect a central mus-
ing, growth, reproduction, and sleep (73,74). Our group has carinic cholinergic component. In this regard, in vivo and in
advanced several lines of evidence suggesting that CRH may vitro data suggest that the muscarinic cholinergic agonist arec-
play a role in the clinical and biochemical manifestations of oline stimulates the HPA axis and that this effect is mediated
melancholia (40, 41, 70-74, 101L As an example, we have mainly by the release of endogenous CRH (36). In addition, it
MECHANISMS OF STRESS 125

appears that the functional activity of ACh and the secretion o f ated (pituitary) hypercortisolism of this disorder causes a sus-
hypothalamic CRH are increased in affective disorders. The tained suppression o f the hypothalamic CRH neuron contributing
physiological relevance o f a CRH-mediated cholinergic stimula- to an atypical depression-like syndrome that is a frequent con-
tion o f the HPA axis is underlined by data showing the involve- comitant of Cushing's disease. In experimental models o f hy-
ment o f cholinergic neurotransmission in both the stress response p o t h y r o i d i s m , we have s h o w n that there is a decrease in
and the pathophysiology o f affective disorders (52, 53, I00, hypothalamic CRH m R N A expression and content in association
116). with a subtle central adrenal insufficiency (96). In chronic fa-
Our group has recently advanced data that some forms o f tigue syndrome, we have shown that a significant decrease in
major depression may not be associated with activation o f stress- 24-hour urinary free cortisol excretion is associated with several
responsive neurotransmitter systems, but rather with their inacti- lines of indirect evidence indicative of a subtle central adrenal
vation. This subtype, termed atypical depression and characterized insufficiency, including robust cortisol responses to low-dose
by evidence o f pathological hypoarousal such as profound leth- ACTH but blunted cortisol responses to high-dose ACTH, and
argy, hypersomnia, and hyperphagia, occurs across the bound- ACTH responses to CRH analogous to those seen in postopera-
aries o f medical illnesses such as Cushing's disease, chronic tive Cushing's disease patients thought to manifest a centrally
fatigue syndrome, hypothyroidism, and seasonal affective disor- mediated adrenal insufficiency (101). Taken together, these data
der (73,74). We have advanced several lines o f evidence that suggest that a second major subtype o f primary affective disor-
these disorders are associated with a functional decrease in the der, namely atypical depression, reflects a pathological inactiva-
responsiveness o f the CRH neuron in these disorders stemming tion rather than a pathological activation of at least one arousal-
from a variety of pathophysiological mechanisms. In Cushing's producing neurotransmitter system that is thought to be a principal
disease, we postulate that the long-standing peripherally medi- effector o f the generalized stress response.

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1984. 15. Bartolome, J. V.; Barotome, M. B.; Daltner, L. A.; Evans, C. J.;
2. Abbott, D. H. Behaviorally mediated suppression of reproduction Barchas. J. D.; Kuhn, C. M.; Schanberg, S. M. Effects of [3-en-
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