Mechanisms Of Stress

Neuroscienceand BiobehavioralReviews, Vol. 16, pp. 115-130, 1992

0149-7634/92 $5.00 + .00 Copyright © 1992 Pergamon Press Ltd.

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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 physical 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)-norepinephrine (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 pathophysiological 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) examine the consequences of stress on the physiologic and behavioral well-being of the organism by integrating knowledge from apparently disparate fields of science. Stress HPA axis Immunosuppression

Autonomic system Depression

Aging

Reproductive suppression

DEFINITION OF STRESS

Growth retardation

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 become more independent of their surroundings, they develop more complex ways of stabilizing their internal environments to counter the changes in their external environment. The importance of adaptive mechanisms was thus recognized as the constancy 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 responsible for coordinating the "fight or flight" response necessary 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 duration, against which the homeostatic mechanisms fail and the organism perishes. Cannon believed that an individual organism's susceptibility to this critical stress "varied under different

A critical problem faced by investigators lies in the definition 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 responses," 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 considered that all matter was a harmonious mixture of elements and qualities (42,65). This early expression of homeostasis was extended 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 nature as causes of disease and referred to the healing forces inherent to the organism as the "healing power of Nature." This

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

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TABLE 2

THE CONCEPT OF HOMEOSTASIS

HISTORY OF THE CONCEPT OF STRESS

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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 Adaptation 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 discharge; 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 pituitary function (83). Saffran and Schally demonstrated in 1955 that a factor from the hypothalamus was regulating ACTH release from the pituitary (166). They named this principle "corticotropin-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 chemical structure was identified, the term "factor" was changed to "hormone." Contemporary theory in stress biology conceptualizes an integrated "stress system" consisting of neuroanatomical and functional structures that function to produce the behavioral, physiological and biochemical changes directed toward maintaining homeostasis (42). This theory is supported by recent findings 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 divisions of the stress system have additional integrative actions. These include complementary and permissive interactions of glucocorticoids and catecholamines in the regulation and maintenance 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 perturbation that disrupts homeostasis. Physical stressors include disturbances of the internal environment (anoxia, hypoglycemia, etc.), external extremes (heat and cold), and multifaceted stressors (noxious stimuli and physical strain, such as exercise or in-

Empedocles (500--430 BC) Hippocrates (460-375 BC) Epicurus (341-270 BC) Claude Bernard (1813-1878) Walter Cannon (1871-1945) Hans Seyle 1907-1982)

first written reference to homeostasis. Health is the state of the harmonious balance of the elements, and disease is the state of dysharmony."Nature heals disease" (Noysvn Fyseiw Iatroi). Coping with emotional stressors improves the quality of life. "Milieu interieur." "Fight or flight" reaction; "homeostasis." The "General Adaptation Syndrome."

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 adaptive, and inhibition of nonadaptive, neural pathways which enable 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 suppression 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 stimulation of cardiovascular and pulmonary function, which include increased heart rate, blood pressure and respiration (218). Simultaneously, anabolic processes, such as digestion, growth, reproduction 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. Containment 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 pathogenic. Thus metabolic (myopathy, fatigue, changes in glycemia) and cardiovascular consequences (hypertension), compromised growth and tissue repair, peptic ulceration, reproductive suppression (impotence and amenorrhea), as well as consequences of immunosuppression (increased susceptibility to infection and cancer) can occur when the state of stress is unduly prolonged (105). In addition to elimination of, or habituation to, the stressor, 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

Psychogenic/ Emotional Stimuli

TABLE 3 BEHAVIORAL AND PHYSIOLOGICAL ADAPTATION DURING STRESS Behavioral Adaptation • Altered cognition and attention span level • Increased alertness • Altered sensory threshold • Sharpened memory and sensation • Stress-induced analgesia • Suppression of feeding behavior • Suppression of reproductive behavior Peripheral Adaptation • Oxygen and nutrients directed to the CNS and stressed body sites • Detoxification from toxic products • Altered cardiovascular tone • Containment of the stress-response

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Homeostasis and the Components of the Stress Response The HPA axis and the sympathetic system are important regulators of an animal's homeostatic functions (205). Thus the organism's response to stress is composed of behavioral, endocrine, and autonomic components, coordinated to neutralize the disrupting effects of the "stressors" on homeostasis (42, 73, 74). Below, we describe the mechanisms by which the various components 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 glucocorticoids. 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-

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I I thetic system, while centrally produced norepinephrine inhibits the sympathetic system via local a2-adrenergic receptor inhibition (203). 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 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 excessive 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 counterregulatory elements (194-196).

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Glucocorico // Adrenal FIG. 1. Schematic representation of the putative regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The corticotropin-releasing hormone (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, behavior 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 normal 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 feedback loop between glucocorticoids and the hypothalamic-pituitary 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 include 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 glucocorticoids at all times, while simultaneously providing an emergency 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 peptide 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 immunocytochemistry, 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 hypophyseal portal vessels. These vessels function as a direct short vascular pathway from the hypothalamus to the anterior pituitary. Thus CRH, which is released into the hypophyseal portal system, is transported to the anterior pituitary, where it stimulates 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 immunocytochemical, 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 ganglia 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 adrenalectomy 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, implicated 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 secretion 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 release 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 cytokines, including Interleukin-1 (IL-I), Interleukin-2 (IL-2), Interleukin-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 beyond 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 cerebroventricular system produces a number of effects that are reminiscent of the stress response (28,29). These include neuronal activation, electroencephalographic arousal, and pronounced general 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 environments (202). At low doses, CRH-induced activation is characterized by increased locomotion, sniffing, grooming and rearing. These changes are believed to be consistent with "'general behavioral arousal." High doses of CRH, on the other hand, produce 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 increases 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 septum, nucleus accumbens, periventricular thalamus, periaqueductal 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 fragment; 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 believed to be specific and determined by local enzymes and pH. ACTH is transported via the systemic circulation to the adrenal gland, where it stimulates synthesis and secretion of glucocorticoids, 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

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reduces exploration in a novel environment without influencing locomotion (57). The increased activity produced by ACTH is about 100 times less potent than the changes produced by CRH.

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FIG. 2. Schematic representation of proopiomelanocortin (POMC), the large molecular weight precursor of ACTH, 13-1ipotropic hormone (13LPH), 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 exposed to regular, fixed doses of ACTH, the glucocorticoid response 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 eliminated, 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 facilitate 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 endocrine systems. When ACTH concentrations are high, receptors are desensitized and are downregulated or disappear. Conversely, when ACTH concentrations are low, the number or sensitivity of the receptors increases. Although the ACTH receptor system appears to follow a normal pattern, the glucocorticoid 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/13endorphin 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 polypeptide (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 stimulates ACTH release synergistically with CRH (177). Glucocorticoids 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 enhance 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 opiate antagonist, and competes with opiate-binding sites in the brain. Thus ACTH can counteract morphine analgesia and reverse catatonic posture (immobility). ACTH administered ICV also appears to affect social behavior in the rat by reducing social interaction and decreasing aggression. Novel or stressful stimuli induce grooming, which has been related to the endogenous release of ACTH (69). The behavioral response to ICV ACTH is characterized by the "stretching yawning syndrome," in which rats display excessive 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

Glucocorticoids The adrenal gland consists of at least two anatomically and chemically distinct structures: an inner medullary area containing catecholamine-producing chromaffin cells and an outer cortical 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 active fraction of the hormone which exerts negative feedback effects 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 system (CNS) are mediated by two separate receptor systems: glucocorticoid 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 response 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/corticosterone), 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 antagonist. The Type I receptors that are found in the circumventricular organs function as mineralocorticoid receptors that respond to aldosterone and act to regulate sodium homeostasis, cardiovascular control and salt appetite (173). With age, the hippocampus 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 concentrations 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 occupancy 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, presumably 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 result in a more persistent elevation of circulating plasma corticosteroid 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 coordination of the circadian patterns of food intake and sleep. The second is a negative feedback effect on stress-activated neural

120

JOHNSON, KAMILARIS, CHROUSOS AND GOLD

circuits and metabolic processes. Interestingly, the acute effects of glucocorticoids are euphorogenic, whereas chronically elevated glucocorticoids produce depression in a large number of subjects (27).

NE

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) nervous 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 associated with conferring an adaptive advantage during stressful situations via its effectors, the sympathetic nerves and the adrenal medulla, located in the periphery. On the other hand, the parasympathetic division of the autonomic nervous system, which is functionally linked to the sympathetic system, appears to produce effects antithetical to those of the sympathetic nervous system. 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 released 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 sympathomedullary 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 adrenal medulla and release of NE from the sympathetic nerve terminals (205). In contrast, chronic intermittent stress is associated with changes in the adrenal medulla, including increased activity of enzymes involved in catecholamine biosynthesis, increased rates of catecholamine synthesis and elevated tissue concentrations of catecholamines (108). Chronic intermittent stressors initially 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 intermittent fashion results in a reduced sympathetic, sympathomedullary 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 animals 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). Experimentally 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 disturbances observed in patients with depression, who frequently report feelings of helplessness or powerlessness to cope with stress. The weight of the available evidence suggests one mechanism underlying the behavioral deficits observed in animals exposed to inescapable stress is a depletion of norepinephrine

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FIG. 3. Schematic diagram of the functional interrelations between corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC-NE) systems. These systems are the principal central biologic effectors of the generalized stress response. In the periphery, both systems act through glucocorticoids secreted from the adrenal cortex and the catecholamines, epinephrine and norepinephrine (E, NE) from the sympathetic 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 system which innervates the prefrontal cortex, a brain region believed 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 implicated 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/hippocampus complex during stress (75). Finally, the LC-NE/sympathetic systems seem to respond similarly to the CRH system to many of the same neurochemical modulators. Serotonin and acetylcholine appear to be excitatory to the sympathetic system (5, 9, 12, 36, 61, 80), while the gabaergic (9,61) and the opioid peptidergic (9, 23, 34, 80) neurotransmissions 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 immunity are directly linked to the stress system, and each is pro-

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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 immunosuppression. In addition, some common psychiatric disorders, 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 suggested that cortisol hypersecretion in aged animals is due to degenerative 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 system, which has been associated with inhibition of the HPA axis (173). With age, the hippocampus loses approximately 50 percent 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 increased 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 glucocorticoids on the hippocampus (173). Early neonatal experience may play a role in shaping individual patterns of stress susceptibility in later life. Meany et al. (125,126) have demonstrated that neonatal handling of rats increases hippocampal glucocordcoid receptor levels. This is concordant 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 disruptive factor in reproductive function. Females under stress may demonstrate delayed puberty, lack of behavioral receptivity, failure of ovulation or embryo implantation, spontaneous abortion, 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 reproduction 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 mechanism(s) of these effects on reproductive function are not fully elucidated, possible sites involved include: 1) a centrally mediated inhibition of gonadotropin-releasing hormone (GnRH) release by CRH, opioids and glucocorticoids (158,161); 2) a glucocorticoid-mediated decrease in pituitary responsiveness to GnRH, resulting in decreased luteinizing hormone (LH) secretion (81); 3) direct gonadal effects of glucocorticoids with subsequent alterations in sex steroid output (13,39); and 4)

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nal ~~'Gonad Target Tissues FIG. 4. Schematic representation of the functional interrelations between the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. CRH activates the pituitary-adrenal axis and GnRH the pituitary-gonadal axis, respectively. The activity of the GnRHsecreting neurons during stress is inhibited by CRH directly or via hypothalamic (arcuate nucleus) [3-endorphin(~-EP). Glucocorticoids suppress the activity of the reproductive axis at all levels, including the hypothalamus, 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 gonadal 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 associated with a significant reduction in LH release, resulting in decreased sexual behaviors in males and lack of behavioral receptiveness and complete ovarian inactivity in females. Similarly, 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 induced inhibition of LH release was not addressed in this study, the fact that exogenous GnRH administration reversed the LHdecrease 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 elevated 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-endorphin) (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 secretion 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 amenorrheic 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. Glucocorticoids 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 Leydig cell function. Leydig cell sensitivity to LH and hCG is decreased by glucocorticoids, probably due to glucocorticoidinduced reductions in testicular LH receptors (13,39). In cycling females, glucocorticoid treatment decreased estradiol concentrations 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 female 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 precipitate premature labor (16, 87, 114). Growth Retardation In humans, linear growth and final adult stature depend on multiple factors. These include genetic constitution (154), nutrition (I 15), systemic disease (32,78), hormones (90) and psychosocial environment (151). A putative association between stressful psychosocial environment and subsequent physical stature, intellectual 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 relationships in the neonatal environment; believed to be of particular 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 impairments: 1) delayed physical maturation, defined by both lower than normal body weight and height and delayed onset of puberty; 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 "functional" growth hormone (GH) deficiency exists, which normalizes 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 hypopituitarism (46). Although abnormalities in thyroid and adrenal

JOHNSON, KAMILARIS, CHROUSOS AND GOLD

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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 somatostatin, which is inhibitory. The activity of GRH neurons during stress appears to inhibited by CRH directly and/or via hypothalamic [3-endorphin (13-EP) and somatostatin. GH exerts peripheral growth-promoting actions directly by stimulating peripheral somatomedin-C (IGF-I) production. 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 probably at the hypothalamus. In addition, glucocorticoids induce major tissue 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 pituitary 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 administration of CRH decreases GH secretion in rats suggests a possible role of endogenous CRH in the modulation of GH secretion during stress (142,159). Studies of the possible mechanisms involved in this effect suggest a central site of action, since specific 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 physiological and behavioral abnormalities in the offspring. For instance, 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

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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 psychosocial growth retardation has been related to unsatisfactory mother-infant relationships, often measured in terms of physical contact (76,77). In nonhuman primates, when physical contact is restrained, even if visual, auditory and olfactory cues are mainmined, 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 omithine decarboxylase activity and GH secretion and reduced tissue 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 sufficiently 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 immunocompetence during stress. Among the effectors of the stress response, the hypothalamic-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 CRHmediated 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 inflammation, 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 effects, as well as the induction of lymphopenia, thymic involution, 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 pituitaryadrenal activation and concomitant glucocorticoid-mediated immunosuppression 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 antagonists or an endogenous deficiency in the responsiveness of the CRH neuron to a variety of immune mediators results in susceptibility 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

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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 response primarily via increases in glucocorticoid secretion. This glucocorticoid-mediated immunosuppression could prevent excessive inflammatory/immune responses during acute stress. (Solid lines represent 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 inflammatory 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 activation of the pituitary-adrenal axis, but also to possess a variety of behavioral effects when given ICV. Specifically, the central administration 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, enhancement of pathways mediating cautious avoidance and anxiety, 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 overshooting, 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 restraint 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 immunologic and behavioral response of the organ to increase the likelihood of survival.

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It has been suggested that patients with major depression show immunosuppression as a consequence of the hypercortisolism frequently associated with this disorder (33). However. the data have been conflicting. Although we cannot definitively account for the discrepancies, they could reflect the fact that glucocorticoids 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 associated 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 association 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 system, although many neurotransmitters participate in the regulation and counterregulation of this important stress responsive system. NE is thought to have a variety of effects on the immunologic response, acting both as a blood-borne humeral mediator 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 pathophysiology of several psychiatric syndromes, such as major depression, anorexia nervosa and panic anxiety, stems from an abnormality in the counterregulation of the generalized stress response, resulting in CRH and/or central catecholamine hypersecretion (192). In particular, it has been hypothesized that abnormalities in the positive regulation of or defects in counterregulation 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 hormonal and behavioral changes closely resemble the symptom complex of depression (71); and 4) hypercortisolism is a consistent feature of the classic form of major depression, melancholia (165). The symptom complex of melancholia indicates that depression need not be a state of pathological inactivation or suppression, as the term depression implies, but rather a state of pathological hyperarousal (73,74). Indeed, from a clinical perspective, 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, prospects of the worthless self. This anxiety about self and the future are associated with other signs of hyperarousal or activation of the generalized stress response that include enhanced vigilance, as well as inhibition of vegetative functions such as feeding, 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 corticotroph 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 reproduces 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, regardless 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 helplessness 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 hypothalamic hypogonadism, shortened REM latency, and a behavioral phenotype compatible with the organism's being overwhelmed by stress (213,214). This syndrome responds to the classic treatments 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 growing body of evidence that suggests that supersensitivity of central muscarinic mechanisms may be involved in the pathophysiology of depressive disorders (52, 53, 91-93). Stress results 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, neuroendocrine, sleep and heart rate profiles may reflect a central muscarinic cholinergic component. In this regard, in vivo and in vitro data suggest that the muscarinic cholinergic agonist arecoline stimulates the HPA axis and that this effect is mediated mainly by the release of endogenous CRH (36). In addition, it

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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 stimulation o f the HPA axis is underlined by data showing the involvement 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 stressresponsive neurotransmitter systems, but rather with their inactivation. This subtype, termed atypical depression and characterized by evidence o f pathological hypoarousal such as profound lethargy, hypersomnia, and hyperphagia, occurs across the boundaries o f medical illnesses such as Cushing's disease, chronic fatigue syndrome, hypothyroidism, and seasonal affective disorder (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-

ated (pituitary) hypercortisolism of this disorder causes a sustained suppression o f the hypothalamic CRH neuron contributing to an atypical depression-like syndrome that is a frequent concomitant of Cushing's disease. In experimental models o f hyp o t h y r o i d i s m , we have s h o w n that there is a decrease in hypothalamic CRH m R N A expression and content in association with a subtle central adrenal insufficiency (96). In chronic fatigue syndrome, we have shown that a significant decrease in 24-hour urinary free cortisol excretion is associated with several lines of indirect evidence indicative of a subtle central adrenal insufficiency, including robust cortisol responses to low-dose ACTH but blunted cortisol responses to high-dose ACTH, and ACTH responses to CRH analogous to those seen in postoperative Cushing's disease patients thought to manifest a centrally mediated adrenal insufficiency (101). Taken together, these data suggest that a second major subtype o f primary affective disorder, namely atypical depression, reflects a pathological inactivation rather than a pathological activation of at least one arousalproducing neurotransmitter system that is thought to be a principal effector o f the generalized stress response.

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