Endocrinology and Metabolism Clinics
Volume 30 • Number 3 • September 2001
Copyright © 2001 W. B. Saunders Company
Address reprint requests to
Kamal E. Habib MD, PhD
Clinical Neuroendocrinology Branch
National Institute of Mental Health
National Institutes of Health Building 10, Room 2D-46
Bethesda, MD 20892-1284
e-mail: habib@codon.nih.gov
PHYSIOLOGY OF THE STRESS RESPONSE
Living organisms strive to obtain and maintain the most optimal circumstances for their well-being. Under favorable conditions, individuals can be invested in vegetative and pleasurable functions that enhance their growth and development and the survival of their species, such as food intake and sex.[14] When the environmental conditions are less optimal, individuals adapt to the circumstances while trying to escape to more advantageous conditions. Adaptive or homeostatic responses are directed at protecting the internal milieu from undergoing changes that endanger the survival of cells and body systems.[19] Adaptive responses to adversity are proportional to the intensity of the stimulus and range from a simple localized reaction to a generalized and systemic state that affects the entire organism.[18]
When faced with excessive demands or threats, a subject's adaptive responses attain a stereotypic nonspecific nature, a state known as ''stress.''[42] Stress is defined as the state in which the brain interprets the quantity of stimulation as excessive or its quality as threatening, thus responding in a generalized way.[18] Biologic, physical, or psychologic stressors generally precipitate similar responses referred to by Selye[90] as ''the general adaptation syndrome.'' During stress, cardiac output and respiration are enhanced, and blood flow is redirected to provide the highest perfusion to the brain and muscular system. The brain focuses on the perceived threat and acts accordingly.[42] Moreover, endocrine programs of pleasure, growth, and reproduction are shut down for the sake of saving energy. Catabolism is enhanced, and fuel is used mostly to supply the aroused brain, heart, and muscles.[19]
The metabolic changes incurred during stress involve the secretion of epinephrine and norepinephrine by the adrenal medulla and the sympathetic nerves, respectively. Both hormones have been associated with the ''fight or flight'' response described by Cannon in 1914. When Selye[90] described stress as the nonspecific generalized response to diverse nocuous stimuli in 1936, the importance of glucocorticoid hormones of the adrenal cortex became evident. Selye pointed to adrenal hypertrophy, thymolymphatic dystrophy, and gastric ulceration as the classic triad of the stress response.[91]
The hypothalamic-pituitary-adrenal (HPA) axis and the sympathoadrenal system serve as the peripheral limbs via which the brain influences virtually every cell in the body during exposure to threatening stimuli.[35] The brain also differentially activates a subset of vagal and sacral parasympathetic efferents that mediate the gut responses to stress.[41A] [41D] Moreover, stress has been known to result in a state of immunosuppression.[26] More detailed work has indicated that stress might boost humoral immunity while suppressing cellular immunity. This response is mediated by a differential effect of stress hormones, the glucocorticoids and catecholamines, on T-helper-1/T-helper-2 cells and type 1/type 2 cytokine production. On the other hand, acute stress is thought to induce proinflammatory activities in certain tissues through neural activation of the peripheral corticotropin-releasing hormone (CRH)-mast cell-histamine axis. Through these mechanisms, stress may influence the onset or course of infectious, autoimmune/inflammatory, allergic, and neoplastic disease.[26]
The brain circuits that initiate and maintain the stress response are illustrated in Figure 1 . They involve the high control centers of the aforementioned peripheral effectors. The hypothalamus controls the secretion of pro-opiomelanocortin (POMC) products that include corticotropin (ACTH) and beta-endorphin from the anterior pituitary corticotrophs. ACTH stimulates the secretion by the adrenal cortex of glucocorticoid hormones, mainly cortisol in humans and corticosterone in rats.[19] The latter hormones have a permissive role on the adrenal medullary secretion of epinephrine. Moreover, the other POMC product, beta-endorphin, may stimulate the adrenal medulla to secrete epinephrine as well.[41A][41C] The locus coeruleus-norepinephrine system controls the stress-induced stimulation of the sympathoadrenal system. The Barrington nucleus, the nucleus tractus solitarius, and the dorsal motor vagal nucleus are thought to control the differential activation of vagal and sacral parasympathetic efferents that mediate the gut responses to stress.[41B] [41D] The amygdala, acting in concert with the hippocampus and the anterior cingulate and prefrontal cortices, mediates the focused attention on the perceived threat, the affective inflexibility, and fear-related behaviors.[7]
The hypothalamus secretes a factor that stimulates ACTH secretion from the anterior pituitary, which, in turn, stimulates the adrenal cortex to secrete large quantities of glucocorticoid hormones.[75] As is true for epinephrine and norepinephrine, cortisol secretion is a marker that a subject is undergoing stress. After several years of intensive research, the hypothalamic factor that stimulates corticotropin secretion was identified and isolated as 41 amino acid peptide by Vale's group[104] and called CRH.
After its release from the hypothalamic paraventricular nucleus (PVN), CRH acts as the principal regulator of anterior pituitary ACTH secretion. Arginine vasopressin (AVP) is a potent synergistic factor with CRH in stimulating ACTH secretion; however, AVP has little ACTH secretagogue activity alone. CRH and AVP may have a reciprocal positive interaction at the level of the hypothalamus, with each neuropeptide stimulating the secretion of the other.[18]
Pro-opiomelanocortin is a precursor gene that encodes not only the stress hormone ACTH but also the opioid peptide beta-endorphin 1-31, as well as alpha, beta, and chi melanocyte-stimulating hormone (MSH).[10] Although the major site of expression of the POMC gene is the pituitary gland, it is also expressed in several brain regions (e.g., the arcuate nucleus) and peripheral tissues (e.g., gut). In the pituitary, the POMC gene is expressed in anterior lobe corticotrophs and in the intermediate lobe. The precursor POMC undergoes a series of posttranslational processing steps to produce its tissue-specific final products.[9] In the corticotroph cells, the cleavage of POMC yields equimolar amounts of a carboxy-terminal glycopeptide called 16K, ACTH 1-39, and beta-lipotropin (beta-LPH). Part of the beta-LPH molecules is further processed in these cells to beta-endorphin 1-31. By contrast, in the intermediate lobe, all of the beta-LPH is converted to beta-endorphin, and ACTH is converted to alpha-MSH and corticotropin-like intermediate lobe peptide (CLIP).[14]
In nonstressful situations, CRH and AVP are secreted in the portal system in a circadian and highly concordant pulsatile fashion.[14] In humans, the amplitude of the CRH and AVP pulses increases in the early morning hours, resulting eventually in increases of the amplitude and apparent frequency of ACTH and cortisol secretory bursts in the general circulation. The circadian release of CRH, AVP, ACTH, and cortisol in their characteristic pulsatile manner is thought to be controlled by one or more pacemakers whose location in humans is not yet known. These diurnal variations are perturbed by changes in lighting, feeding schedules, and activity, and are disrupted by stress.[18]
During acute stress, the amplitude and synchronization of the paraventricular nucleus (PVN) CRH and AVP pulsations in the hypophyseal portal system markedly increases.[16] [17] [18] [19] With strong physical stress, especially that associated with hypotension or a decrease of blood volume, recruitment of AVP of magnocellular neuron origin secreted into the hypophyseal portal system via collateral neuraxons and into the systemic circulation takes place. Depending on the type of stress, other factors such as angiotensin II and various cytokines and lipid mediators of inflammation are secreted and act on hypothalamic, pituitary, or adrenal components of the HPA axis, potentiating its activity for the most part.[34]
The adrenal cortex is the principal target organ of pituitary-derived circulating ACTH.[37] The latter hormone is the key regulator of glucocorticoid and adrenal androgen secretion by the zona fasciculata and reticularis, respectively, and also participates in the control of aldosterone secretion by the zona glomerulosa. Other hormones or cytokines, originating from the adrenal medulla or coming from the systemic circulation, with or without neuronal information from the autonomic nerves of the adrenal cortex, may also participate in the regulation of cortisol secretion.[54]
Glucocorticoids are the final products of the HPA axis. They are pleiotropic hormones and exert their effects through ubiquitously distributed intracellular receptors. The nonactivated glucocorticoid receptor resides in the cytosol in the form of a hetero-oligomer with heat shock proteins and immunophilins. On ligand binding, the glucocorticoid receptors dissociate from the rest of the hetero-oligomer and translocate into the nucleus, where they interact as homodimers with specific glucocorticoid-responsive elements within the DNA to activate appropriate hormone-responsive genes. The activated receptors also inhibit, by protein-protein interactions, several transcription factors, such as c-jun/ c-fos and NF-kB, which are positive regulators of the transcription of several genes involved in the function and growth of nonimmune and immune cells.[108] They also change the stability of mRNAs and, hence, the translation rates of several glucocorticoid-responsive proteins. Furthermore, glucocorticoids influence the secretion rates of specific proteins and alter the electrical potential of neuronal cells through mechanisms that remain to be elucidated.[39]
Glucocorticoids have a key regulatory role in the basal control of HPA axis activity and in the termination of the stress response by acting on extrahypothalamic regulatory centers, such as the hippocampus and frontal cortex, the hypothalamus, and the pituitary gland (Fig. 1) .[16] The inhibitory glucocorticoid feedback on the ACTH secretory response acts to limit the duration of the total tissue exposure to glucocorticoids, minimizing the catabolic, lipogenic, antireproductive, and immunosuppressive effects of these hormones. A dual receptor system exists for glucocorticoids in the central nervous system, including the glucocorticoid receptor type I, or mineralocorticoid receptor, which responds positively to low levels of glucocorticoids, and the classic glucocorticoid receptor (type II), which responds to basal and stress levels. The latter receptor participates in the negative feedback control of the HPA axis via activation of an afferent GABAergic pathway to the PVN.[61] [78]
The autonomic nervous system responds rapidly to stressors and controls a wide range of system functions.[101] Most of the gut functions are inherently regulated by the enteric nervous system, which has wide projections to the brain. Cardiovascular, respiratory, renal, endocrine, and other systems are regulated by the sympathetic nervous system, the parasympathetic system, or both. Because of paradoxic effects, in many instances, the parasympathetic system may assist sympathetic functions by withdrawing and can antagonize them by increasing its activity.[54][101] During severe stress, the vagus mediates some sympathetic-like effects in the gastrointestinal system, such as the suppression of gastric secretion.[41A] [41C]
Sympathetic innervation of peripheral organs is derived from the efferent preganglionic fibers, whose cell bodies lie in the intermediolateral column of the spinal cord. These nerves synapse in the bilateral chains of sympathetic ganglia with postganglionic sympathetic neurons that widely innervate the smooth muscle of the vasculature, the heart, skeletal muscles, kidney, gut, fat, and many other organs. The preganglionic neurons are primarily cholinergic, whereas the postganglionic neurons are mostly noradrenergic. The sympathetic system also has a humoral contribution by providing most of the circulating epinephrine and some of the norepinephrine from the adrenal medulla.[16]
In addition to the classic neurotransmitters acetylcholine and norepinephrine, the sympathetic and parasympathetic subdivisions of the autonomic nervous system include several subpopulations of target-selective and neurochemically coded neurons that express a variety of neuropeptides and in some cases, ATP, nitric oxide, or lipid mediators of inflammation. CRH, neuropeptide Y (NPY), and somatostatin are found in postganglionic noradrenergic vasoconstrictive neurons. Transmission in sympathetic ganglia is also modulated by neuropeptides released from preganglionic fibers and short interneurons, as well as by primary afferent nerve collaterals.[17]
NEUROENDOCRINE CONTROL OF THE STRESS RESPONSE
The stress response is global and affects all body systems. Within seconds, several processes are elicited. Characteristic processes of the stress response include mobilization of stored energy with inhibition of subsequent energy storage and gluconeogenesis, sharpened focused attention on the perceived threat, increased cerebral perfusion rates and cerebral glucose use, enhanced cardiovascular output and respiration, enhanced delivery of energy substrates to the muscles, inhibition of reproductive physiology and behavior, modulation of immune function, and decreased feeding and appetite. In the situation of fluid loss, such as hemorrhage, water retention occurs through renal and vascular mechanisms.[54] [101]
The orchestrated interplay of several neurotransmitter systems in the brain (Fig. 1) underlies the characteristic phenomenology of behavioral, endocrine, visceral, autonomic, and immune responses to stress. These transmitters include CRH, AVP, opioid peptides, dopamine, and norepinephrine. Outside the brain, there is enhanced pituitary secretion of prolactin and pancreatic secretion of glucagon. Moreover, there is global reduction of NPY in the brain and decreased hypothalamic release of gonadotropin-releasing hormone (GnRH), followed by reduced secretion of pituitary gonadotropins. In hemorrhagic stress, there is additionally marked activation of the renin-angiotensin system.[19]
Corticotropin-Releasing Hormone
Shortly after its isolation, several clues indicated that CRH was implicated in other components of the stress response, such as arousal[92] and autonomic activation.[6] Supportive evidence was initially derived from numerous studies that reported precipitation of several responses characteristic of stress after intracerebroventricular or selective brain administration of CRH in rodents and nonhuman primates. More convincing evidence demonstrated suppression of many aspects of the stress response after brain administration of CRH peptide antagonists. More recently, it has been found that CRH type 1 receptor (CRH-R1) knock-out mice have a markedly deficient ability to mount an effective stress response.[96]
Several hypothalamic nuclei contain CRH cell bodies, including the medial preoptic area, dorsomedial nucleus, the arcuate nucleus, the posterior hypothalamus, and the mamillary nuclei. The PVN of the hypothalamus contains most of the CRH cell bodies that stimulate anterior pituitary hormone secretion of ACTH. These neurons originate in the parvocellular region of the PVN and send axon terminals to the capillaries of the median eminence. CRH is also present in a small group of PVN neurons that project to the lower brain stem and spinal cord. These latter neurons are involved in regulating autonomic nervous system function.[102]
Corticotropin-releasing hormone cell bodies are also present in the central nucleus of the amygdala, the substantia innominata, and the bed nucleus of the stria terminalis. CRH neurons in the central nucleus of the amygdala project to the parvocellular regions of the PVN and the parabrachial nucleus of the brain stem. These projections may account for CRH neuroendocrine, autonomic, and behavioral effects. CRH neurons originating in the bed nucleus of the stria terminalis send terminals to the parabrachial nuclei and dorsal vagal complex in the brain stem to coordinate autonomic activity. CRH fibers also interconnect the amygdala with the bed nucleus of the stria terminalis and the hypothalamus.[40] [84]
Corticotropin-releasing hormone neurons in the cerebral cortex may be important for the behavioral actions of the peptide. CRH interneurons are contained in the second and third layers of the cerebral cortex and project to layers I and IV. In addition, scattered CRH cells are present in the deeper layers of the neocortex. The highest density of CRH-containing neurons is found in the prefrontal, insular, and cingulate areas. The distribution of CRH in these areas may explain its effects on cognitive processing.[86] [100]
In addition to their wide distribution in the cerebrum, several groups of CRH neurons are located throughout the brain stem and in the spinal cord. In the midbrain, CRH cells are found in the Edinger-Westphal nucleus, the periaqueductal gray, and the dorsal raphe nucleus. In the pons, CRH cell bodies in the parabrachial nucleus project to the medial preoptic nucleus of the hypothalamus. The locus coeruleus norepinephrine system also contains CRH neurons that may mediate the cross-talk between the two systems. In the medulla, CRH neurons are known to exist in the nucleus of the solitary tract and the dorsal vagal complex, in addition to some scattered groups in the reticular formation and the spinal trigeminal nucleus. CRH cell bodies are found in laminae V, VI, VII, and X of the spinal cord, as well as in the intermediolateral column of the thoracic and lumbar regions. Spinal CRH neurons may have an important role in modulating sensory input via ascending projections to the thalamus and the brain stem reticular formation.[18] [84]
Stress is a potent general activator of CRH release from the hypothalamus and extrahypothalamic sites.[42] The mechanisms via which stress stimulates CRH neurons are unclear. Whether CRH or another transmitter (e.g., norepinephrine) is upstream in eliciting the neurocircuitry of stress remains to be determined.
Binding sites for CRH are found in the anterior pituitary, throughout the brain, and in various peripheral sites, such as the adrenal medulla, prostate, gut, spleen, liver, kidney, and testes. CRH receptors belong to the seven-transmembrane G protein-coupled family of receptors, in which CRH binding stimulates the intracellular accumulation of cAMP. Two distinct CRH receptor subtypes designated CRH-R1 and CRH-R2 have been characterized. Distinct genes that are differentially expressed encode the two receptor subtypes.[102]
The subtype CRH-R1 is widely distributed in rat brain, mainly in neocortex and cerebellum. CRH-R1 is the most abundant subtype found in the anterior pituitary. CRH-R2 receptors are expressed mainly in the peripheral vasculature and the heart, as well as in subcortical structures in brain, such as the septum, amygdala, and hypothalamus in rodents. In nonhuman primates, CRH-R2 is found in central and peripheral locations. The CRH-R2 receptor has been found in the human amygdala. In the rhesus monkey, CRH-R1 and CRH-R2 receptors are found in the pituitary, neocortex, amygdala, and hippocampus. CRH-R1, but not CRH-R2, receptors are present in locus coeruleus, cerebellar cortex, thalamus, and striatum. CRH-R2, but not CRH-R1, receptors are found in the choroid plexus and bed nucleus of the stria terminalis.[12] [89A] [95] [115] [116]
Central administration of small doses of CRH produces a profound increase in locomotor activity. Conversely, high doses of CRH produce a dramatic decrease in locomotion.[23] [65] Intracerebral CRH injections produce additional behavioral effects, including increases in sniffing, grooming, and rearing in a familiar environment and the assumption of a freeze posture, decreased feeding and sexual behavior, and increased conflict behavior in an unfamiliar environment. The behavioral effects of CRH are not indirect consequences of its actions on the pituitary because they are not seen after pretreatment with doses of dexamethasone that adequately block pituitary-adrenal activation. Most of the aforementioned effects of CRH can be blocked by administration of CRH peptide antagonists, strongly supporting a specific CRH receptor-mediated event in these behaviors. Furthermore, the CRH receptor antagonist attenuates many of the behavioral consequences of stress, which underscores the role of endogenous peptide in mediating many of the stress-related behaviors.[42]
CRH acts in the brain to activate the sympathetic nervous system, with subsequent stimulation of epinephrine secretion from the adrenal medulla and noradrenergic outflow to the heart, kidney, and vascular beds.[7] Other consequences of central administration of CRH include increases in mean arterial pressure and heart rate. In contrast, CRH acts in the brain to inhibit cardiac parasympathetic nervous activity. Peripheral administration of CRH causes vasodilation and hypotension in a variety of species, including humans.[61] [62] The physiologic role of CRH in regulating the autonomic nervous system is supported by data demonstrating central effects of the CRH receptor antagonist alpha-helical CRH (9-41) in attenuating stress-induced adrenal epinephrine secretion.[28]
Corticotropin-releasing hormone stimulates the electrical activity of neurons in various brain regions that contain CRH and CRH receptors, including the locus coeruleus, hippocampus, cerebral cortex, and hypothalamus, as well as lumbar spinal cord motor neurons.[32] In contrast, CRH had inhibitory actions in the lateral septum, thalamus, and hypothalamic PVN. Centrally administered CRH increases the spontaneous discharge rate of the locus coeruleus-norepinephrine system in anesthetized and unanesthetized rats. Activation of the locus coeruleus-norepinephrine system results in arousal and increased vigilance; its dysfunction has been implicated in the pathophysiology of depression and anxiety.[2] [25] [93] [105]
Corticotropin-releasing hormone causes a generalized increase in electroencephalographic activity associated with increased vigilance and decreased sleep time. At CRH doses below those affecting locomotor activity or pituitary-adrenal function, rats remain awake and vigilant, and display decreases in slow-wave sleep. Higher doses of CRH induce seizure activity that is indistinguishable from seizures produced by electrical kindling of the amygdala, which further confirms the role of CRH in brain activation.[24] [32] [50] [85]
The mechanisms by which stress turns on, and termination of stress turns off, CRH brain systems are unclear; however, scattered pieces of information regarding the control of CRH secretion by other transmitter systems have been obtained. Gamma-amino-butyric acid (GABA) agonists and benzodiazepines exert an inhibitory effect on CRH neurons, whereas cholinergic and serotonergic neurons stimulate CRH release. Norepinephrine and opioid peptides have stimulatory and inhibitory effects on CRH release, depending on the dose administered and the receptor subtype involved. Glucocorticoids are potent inhibitors of CRH release from the PVN. The inhibition of CRH release by glucocorticoids is mediated directly at the level of the PVN of the hypothalamus, as well as indirectly through actions on CRH receptors in the hippocampus. Glucocorticoids exert a stimulatory role on CRH neurons in the amygdala and perhaps in the locus coeruleus-norepinephrine system. The latter effects may be of fundamental importance in perpetuating the effects of severe stress by creating a positive feedback loop between CRH and norepinephrine systems.[9] [11] [97]
Under normal conditions, there is a balance between CRH peptide availability and CRH receptor density. Stress or adrenalectomy results in hypersecretion of CRH and a consequent decrease in availability receptors in the anterior pituitary. Likewise, chronic administration of corticosterone causes dose-dependent decreases in anterior pituitary CRH receptor number. In contrast, lesions of the PVN that result in dramatic reductions in hypothalamic CRH secretion increase the density of pituitary CRH receptors.[18] The effects of CRH and products of pituitary-adrenal activation on brain CRH receptors that mediate the behavioral and autonomic aspects of the peptide may be different, that is, increases rather than decreases its own receptors.[42]
Locus Ceruleus-Norepinephrine System
The locus coeruleus and other noradrenergic cell groups of the medulla and pons are collectively known as the locus coeruleus-norepinephrine system. This system is believed to contribute the majority of norepinephrine in the brain because plasma norepinephrine cannot cross the blood-brain barrier. Brain norepinephrine serves globally as an emergency or alarm system that leads to decreases in neurovegetative functions, such as eating and sleeping, and that contributes to accompanying increases in autonomic and neuroendocrine responses to stress, including HPA axis activation. Norepinephrine also activates the amygdala, the principal brain locus for fear-related behaviors. In addition, norepinephrine release during stress inhibits the medial prefrontal cortex and, by so doing, may interfere with two of its key functions (i.e., the shifting of mood from one state to the other based on internal and external cues and the generation of novel complex behaviors).[19] [34] Moreover, by enhancing the long-term storage of aversively charged emotional memories in sites such as the hippocampus and striatum, norepinephrine may contribute to subsequent vulnerability to stress in certain subjects by facilitating the recall of traumatic experiences.[13] [35][36] [52]
Reciprocal reverberatory neural connections exist between the PVN CRH and brain stem noradrenergic neurons of the central stress system, with CRH and norepinephrine stimulating each other, the latter primarily through beta1-noradrenergic receptors. Autoregulatory ultrashort negative feedback loops are also present in the PVN CRH and brain stem nonadrenergic neurons, with collateral fibers inhibiting CRH and catecholamine secretion, respectively, by way of presynaptic CRH and alpha2-noradrenergic receptors. The CRH and catecholaminergic neurons receive stimulatory innervation from the serotonergic and cholinergic systems and inhibitory input from the GABA/benzodiazepine and opioid peptide neuronal systems of the brain.[14] [18]
Arginine vasopressin parvocellular neurons of the PVN of the hypothalamus have an important role in response to most stress modalities. In addition to the role of magnocellular AVP neurons in conserving body fluids and controlling plasma osmolality, PVN AVP serves as another hypothalamic secretagogue of ACTH. AVP synergizes with CRH during stress to stimulate the secretion of abundant quantities of ACTH.[60]
Arginine vasopressin release from axon terminals in the median eminence enters the portal blood system and is carried to the anterior lobe of the pituitary gland, where it acts as a secretagogue for ACTH by binding to V1b receptors. A subset of PVN parvocellular neurons synthesizes and secretes CRH and AVP, whereas another subset secretes CRH or AVP only. The relative proportion of the subset that secretes both neuropeptides increases significantly during stress. The terminals of the parvocellular PVN CRH and AVP neurons project to different sites, including the noradrenergic neurons of the brain stem and the hypophyseal portal system in the median eminence.
Paraventricular nuclei CRH and AVP neurons also send projections to activate POMC-containing neurons in the arcuate nucleus of the hypothalamus, which, in turn, reciprocally project to the PVN CRH and AVP neurons, innervate locus coeruleus-norepinephrine system neurons of the central stress system in the brain stem, and terminate on pain control neurons of the hind brain and spinal cord. During hypovolemic stress, AVP becomes the principal ACTH secretagogue. Moreover, during chronic or prolonged stress, there may be a shift in control of ACTH from CRH to AVP.[44] [60] [71]
In addition to its endocrine and metabolic roles, AVP has been implicated in some of the behavioral responses to stress. Intracerebroventricular injections of picogram doses of AVP induce long-lasting facilitation of learned passive avoidance behavior in rats. In contrast, central antagonism of AVP attenuates conditioned avoidance behaviors. Additionally, AVP has been suggested to have a role in the control of male territorial displays and aggression.[32]
Neuropeptide Y (NPY) is emerging as an important neuromodulatory agent that affects behavior, anterior pituitary hormone secretion, autonomic control, and other neurotransmitter systems. Several studies have shown alterations of central NPY in stress and mental illness.[110] [111] NPY has also been suggested to have an important role in circadian rhythms via its pathway from the thalamic ventrolateral geniculate to the hypothalamic suprachiasmatic nucleus. Most remarkably, mammals injected centrally with NPY eat excessively, probably by modulating the feeding centers in the hypothalamus. Indeed, the magnitude of NPY-induced feeding is higher than that induced by any pharmacologic agent previously tested.[45]
Early studies suggested that NPY increased hypothalamic CRH, and that intra-PVN NPY administration increased plasma ACTH and corticosterone in the rat.[41] Several other lines of evidence have recently suggested an anxiolytic role for NPY in the brain.[5] [110] [117] As an example, a strong negative correlation has been seen between anxiety scores and NPY levels in the cerebrospinal fluid of depressed patients. Anxiety is a core component of the depressive syndrome, and the two psychopathologic states may share a common biologic basis because both respond to classic antidepressant treatment. Local microinjections of NPY into the central nucleus of the amygdala reproduced the anxiolytic-like effect of intracerebroventricular injections but did not affect food intake. The actions of NPY on appetite and anxiety can be anatomically and functionally separated and seem to be independent of each other. The anxiolytic-like actions of NPY are most likely mediated by Y1 receptors in the amygdala.[45] [46] [82] [111]
The mesocortical and mesolimbic components of the dopaminergic system are innervated and activated by the locus ceruleus-norepinephrine system and PVN CRH systems and by glucocorticoids during stress. The mesocortical system, which includes dopaminergic neurons of the ventral tegmentum that send projections to the prefrontal cortex, is thought to be involved in anticipatory phenomena and cognitive functions and to exert a suppressive effect on the stress system. The mesolimbic system, which consists of dopaminergic neurons also of the ventral tegmentum that innervate the nucleus accumbens, is thought to have a principal role in motivational reinforcement and reward phenomena.[18] Euphoria or dysphoria are presumably mediated by the mesocorticolimbic system, which is also the target of several substances of abuse, such as cocaine.[34]
The amygdala nuclei are activated during stress primarily by ascending catecholaminergic neurons originating in the brain stem, or by inner emotional stressors possibly generated in cortical association areas.[16] Activation of the amygdala is important for retrieval and emotional analysis of relevant information for any given stressor.[52] In response to emotional stressors, the amygdala can directly stimulate central components of the stress system and influence the activity of the mesocorticolimbic dopaminergic system, possibly in a lateralized fashion. CRH peptidergic neurons in the central nucleus of the amygdala respond positively to glucocorticoids, and their activation leads to anxiety, fear, and stimulation of the stress system. The hippocampus exerts an important, mostly inhibitory, influence on the activity of the amygdala and of the PVN CRH and locus coeruleus-norepinephrine systems.[8] [66] [76] [89] [107]
Paraventricular nuclei CRH/AVP-producing neurons and locus coeruleus-norepinephrine system neurons reciprocally innervate and are innervated by opioid peptide (POMC-producing) neurons of the arcuate nucleus of the hypothalamus.[19] Activation of the stress system stimulates hypothalamic POMC-peptide secretion, which reciprocally inhibits the activity of central components of the stress system and, through projections to the hindbrain and spinal cord, produces analgesia. POMC peptides also stimulate the mesocorticolimbic system and may produce euphoria and dependence.[80]
Substance P inhibits the PVN CRH neuron, whereas it activates the locus coeruleus-norepinephrine system.[18] Presumably, substance P is elevated centrally when there is peripheral activation of somatic afferent fibers; therefore, it may contribute to changes in the stress system activity in chronic inflammatory or painful states.[48]
Activation of the PVN CRH/AVP and locus coeruleus-norepinephrine systems elevates core temperature.[18] Noradrenaline and CRH, when given intracerebroventricularly, can cause core temperature increases, possibly through prostanoid-mediated actions on the septal and hypothalamic temperature regulating centers. CRH has been shown to mediate to some extent the pyrogenic effects of the inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6), all of which can be stimulated by lipopolysaccharide, which is a bacterial pyrogen.[27]
Prolonged physical and psychologic stress can reduce core temperature, at least in rodents. This response is thought to result from rapid energy loss that exceeds the organism's ability of generating temperature from catabolic processes. Reduction of the body core temperature may provide a protective mechanism to restrain overshooting of the stress response by markedly slowing the metabolic functions of different systems; however, such stress-induced hypothermia may result in activation of other transmitter systems, such as thyrotropin-releasing hormone (TRH), which is known to induce gastric ulceration, a common consequence of severe and prolonged stress in different species.
Usually, marked suppression of food intake occurs during stress. This response is probably an effect on the appetite/satiety centers in the brain. CRH may be the endogenous mediator of the stress-induced inhibition of food intake.[103] CRH administration causes profound anorexia in macaques.[33] Suppression of NPY secretion is likely to be involved as well. NPY inhibits the locus coeruleus-norepinephrine system and activates the parasympathetic system, actions that help with digestion and storage of nutrients.[56] [82]
The more advanced a species is in the evolutionary chain, the more developed is the brain. Humans enjoy the highest level of cortical contribution to information processing. Because the well-developed cortical systems are responsible for sophisticated social skills and constitute the substrates for the psyche, humans are particularly social, and the optimum conditions for their functioning usually involve significant others. Likewise, because of their well-developed psyche and rich learning experiences, humans are aware of subtle social cues that can affect their self-esteem.
In most species, parental care is essential for adequate growth and development of the young.[53] In primates, positive peer interactions are necessary from childhood through adulthood.[81] In adulthood, most humans seek comfort and pleasure with significant others. Such social interactions create states of codependence that make the presence of significant others necessary for the optimal functioning of an individual.
The specific nature of the aforementioned relationships conditions the brain to perceiving the presence of significant others as a cue of security and pleasure. The loss, or even potential loss, of love is usually perceived by the brain as a threat and activates the same stress neurocircuitry as other modalities of stress.
Another common form of psychologic stress is that associated with threats to the self-esteem of the individual. Such threats generate a state of fear of losing control over one's environment. The perception of a threat elicits stress circuits in the brain. Human subjects vary widely in regards to their subjective perception of threats. The authors believe the balance between two different forces, namely, stress and resilience, determines the subject's vulnerability to stress. Genetic and environmental influences, particularly at critical periods of development, contribute to the psychologic make-up characteristic of every individual.[18]
Emotions are processed in the limbic system and its widespread projections in the brain. These projections include the sensory thalamic nuclei, the basolateral and central amygdala nuclei, the locus coeruleus, the hippocampus, and the hypothalamus and associated cortical areas, such as the medial prefrontal cortex. These same nuclei make up the stress neurocircuitry, which may explain why emotional threats are particularly effective in mobilizing the stress system in humans.[19]
Several factors that determine the stress responses of individuals are inherited, as suggested by quantitative genetics of human complex behaviors. It has been estimated that about one half to two thirds of reliable variance in measured personality traits is caused by genetic influences.[18] Genetic polymorphisms and clinically significant alterations in the expression of genes are involved in the regulation of the stress system. A significant amount of the variance of the stress responses of individuals is also environmental, including early life and later life events with long-term or permanent effects. The intrauterine period, infancy, childhood, and adolescence are periods of increased brain plasticity; abnormal activation of the stress system during these critical periods may have profound effects on its function throughout the life of an individual, causing predisposition to pathologic states.[18]
In these formative stages of development, exposure to psychosocial trauma sets into motion a cascade of mental changes that frequently results in long-term predisposition to anxiety, depression, or other stress-associated somatic illnesses.[74] Despite the lack of an explanation for this phenomenon, several studies have shown an association between the patterns of activity of the HPA axis and mood and anxiety disorders.[47]
In nonhuman primate models, separation of mother-reared infants from their mothers is a potent stressor that causes severe behavioral disruptions. Immediately after separation, a protest stage occurs, which is manifested by anxiety and agitation, with increased locomotion, vocalization, and distress calling, probably reflecting the infant's attempts to return to its mother. This phase lasts for 24 to 48 hours and is followed by a stage of despair, marked by significant decreases in locomotion, vocalization, and food intake. Repetitive exposure to such social separation results in progressive exaggeration of the infant's behavioral and neuroendocrine responses to stress.[99]
Macaque infants reared apart from their mothers and raised only with peers typically exhibit biologic and behavioral changes similar to those seen in depression (hypercortisolemia, withdrawal, anxiety, and fearfulness), particularly on exposure to psychosocial stress. Interestingly, disruption of the social bonds between these peer-reared infants (peer separation) results in behavioral responses that are more extreme than the responses of mother-reared infants to maternal separation. Long-term biologic and behavioral features associated with these animals' responses to challenge seem strikingly similar to those reported for patients with a positive history of trauma and abuse.[49] [81]
Central CRH and norepinephrine systems, together with peripheral secretion of large amounts of glucocorticoids and catecholamines, affect virtually every cell in the body.[19] Extensive use of energy stores occurs in several organs, which requires additional oxygen and fuel. The heart rate is accelerated and its contractility enhanced. Respiratory rate increases, and the bronchi are dilated for better oxygenation. Significant changes in blood flow are encountered for redistribution of nutrients and oxygen. Activation of the HPA axis has profound inhibitory effects on the inflammatory immune response because virtually all of the components of the immune response are inhibited by cortisol.[27] At the cellular level, alterations of leukocyte traffic and function, decreases in the production of cytokines and mediators of inflammation, and inhibition of the latters' effects on target tissues are among the main anti-inflammatory and immunosuppressive effects of glucocorticoids (Fig. 2) (Figure Not Available) . These effects are exerted at the resting and basal states and during inflammatory stress, when the circulating concentrations of glucocorticoids are elevated. Stress is also associated with marked disturbance of visceral functions.[87]
Corticotropin-releasing hormone has been localized in a variety of peripheral tissues other than the hypothalamic fibers that innervate the intermediate lobe of the pituitary. CRH has been found in the adrenal medulla of a variety of species and has been reported to increase following stimulation of the splanchnic nerve and hemorrhagic stress. CRH-like immunoreactivity and CRH mRNA have been detected in lymphocytes, where they may have a role in regulating immune function (Fig. 2) (Figure Not Available) . Other tissues in which CRH has been localized include the testis (Leydig cells and advanced germ cells), pancreas, stomach, and small intestine.[1] Although CRH is not detected in the circulation under normal circumstances, high levels have been measured in the plasma of pregnant women, probably originating from the placenta.[73]
The gastrointestinal tract is one of the most vulnerable sites in responding to psychologic adversity[29] (Fig. 3) . It is common for humans to respond to psychologic adversity by experiencing nausea. Diarrhea frequently accompanies fear as well. A serious complication of severe trauma or life-threatening stress is gastric mucosal disruption and bleeding, known as stress ulcer.
In preclinical rodent models, stress is associated with inhibition of gastric secretion and motility, inhibition of small intestinal motility, and enhancement of large bowel transit. Other responses include mucin depletion, diminution of mucosal blood flow, mast cell degranulation, oxidative injury, and increased susceptibility to inflammation and stress ulceration.[88] CRH administration reproduces many of the aforementioned responses, and CRH-R1 antagonism suppresses stress ulceration, mucin depletion, and colon transit. These findings indicate that endogenous CRH-R1 activity is responsible for most of the gastrointestinal responses to stress (K.E. Habib, MD, et al, submitted).
The authors' working hypothesis (Fig. 4) suggests that stress selectively activates a subset of vagal efferents that stimulate the release of certain chemical transmitters from a specific population of enteric nervous system neurons that are particularly responsive to stress. These latter neurons affect the physiologic pattern of smooth muscle contractility. The electric pattern spreads to other segments of the gastrointestinal tract, altering their contractility as well. The transmitters released by these stress-responsive enteric neurons elicit the release of various mediators from immune cells (e.g., 5-HT, PAF, reactive oxygen species, amines) that synergize to cause tissue damage.
Ultimately, two common pathways precipitate gastrointestinal tract manifestations of stress. First, exposure of otherwise isolated nerve endings to inflammatory mediators results in a decrease of their threshold and an increase in their afferent discharge to the brain and other peripheral synapses, causing false activation of certain reflexes (e.g., gastrocolic reflex that normally enhances colon transit in response to gastric distension). Second, alteration of membrane permeability occurs, with subsequent intracellular acidosis, edema, and failure of active pump systems. These changes result in diminution of barrier function and allow diffusion of luminal contents into the gut wall, causing further irritation, immune cell activation, and tissue damage. Preliminary evidence suggests that CRH may be the native transmitter stimulating the stress-responsive vagal efferents in the brain and may perhaps be released from the stress-responsive enteric neurons.[41E]
The reproductive axis is inhibited at all levels by various components of the HPA axis (Fig. 5) (Figure Not Available) . Either directly or through arcuate POMC neuron beta-endorphin, CRH suppresses the GnRH neurons of the arcuate and preoptic nuclei. Glucocorticoids exert inhibitory effects at the levels of the GnRH neuron, the pituitary gonadotroph, influencing primarily the secretion of luteinizing hormone (LH) and the gonads themselves and rendering target tissues of sex steroids resistant to these hormones. CRH is also a potent negative regulator of LH effects in Leydig cells. LH stimulates directly the secretion of serotonin, which acts on 5-HT2 receptors to stimulate the secretion of CRH. This inhibitory loop serves to attenuate androgen production by gonadotropin.[19]
During inflammatory stress, the inflammatory cytokines suppress reproductive function at several levels. These effects are exerted directly and indirectly by activating hypothalamic neural circuits that secrete CRH and POMC-derived peptides, as well as by peripheral elevations of glucocorticoids.[27]
Pregnancy in the third trimester is another condition characterized by hypercortisolism and is the only known physiologic state in humans in which CRH circulates in plasma at levels high enough to cause activation of the HPA axis. Although circulating CRH, which is of placental origin, is bound with high affinity to CRH-binding protein, the circulating free fraction is sufficient to explain the observed escalating hypercortisolism when the concentration of CRH-binding starts to decrease gradually in plasma after the 35th week of pregnancy. Placental CRH may have a role in precipitating labor. Administration of CRH-R1 antagonists in fetal sheep has been shown to delay the onset of parturition.[20]
Suppression of gonadal function caused by chronic HPA activation has been demonstrated in highly trained runners of both sexes, in ballet dancers, and in individuals sustaining anorexia nervosa or starvation. These subjects have increased evening plasma cortisol and ACTH levels, increased urinary free cortisol excretion, and blunted ACTH responses to exogenous CRH; males have low LH and testosterone levels, and females have hypogonadotrophic hypogonadism and amenorrhea. Characteristically, obligate athletes go through withdrawal symptoms and signs if, for any reason, they have to discontinue their exercise routine. This syndrome is possibly the result of withdrawal from the daily exercise-induced secretion of POMC-derived peptides and mesocorticolimbic system dopamine.[57] [58] [63]
The interaction between CRH and the reproductive axis seems to be bidirectional. The presence of estrogen-responsive elements in the promoter area of the CRH gene and direct stimulatory estrogen effects on CRH gene expression have been shown. This finding implicates the CRH gene and the HPA axis as a potentially important target of gonadal steroids and a potential mediator of gender-related differences in the stress response and HPA axis activity.[15] [16]
The growth axis is also inhibited at many levels during stress (Fig. 6) (Figure Not Available) . Prolonged activation of the HPA axis leads to suppression of growth hormone secretion and inhibition of somatomedin C and other growth factor effects on their target tissues by glucocorticoids, the latter possibly through inhibition of the c-jun/c-fos heterodimer by the ligand-bound glucocorticoid receptor.[18] Acute elevations of growth hormone concentration in plasma may occur at the onset of the stress response or after acute administration of glucocorticoids, presumably through stimulation of the growth hormone gene by glucocorticoids through glucocorticoid-responsive elements in its promoter region. In addition to the direct effects of glucocorticoids, which are pivotal in the suppression of growth observed in prolonged stress, increases in somatostatin secretion caused by CRH, with resultant inhibition of growth hormone secretion, have been implicated as a potential mechanism of stress-related suppression of growth hormone secretion.[19]
In several stress system-related mood disorders with a hyperactive HPA axis, such as chronic anxiety or melancholic depression, growth hormone and IGF-1 levels are significantly decreased. When compared with normal control subjects, patients with panic disorder have blunted growth hormone responses to intravenously administered clonidine, and children with anxiety disorders might not attain their final height potential. In melancholic depression, growth hormone secretion is decreased, and the dexamethasone-induced growth hormone increase is blunted.[4][16]
Glucocorticoids have profound inhibitory effects on growth hormone and gonadal steroid production and antagonize the actions of these hormones on fat tissue catabolism (lipolysis) and muscle and bone anabolism. Chronic activation of the stress system would be expected to increase visceral adiposity, decrease lean body (bone and muscle) mass, and suppress osteoblastic activity (Fig. 7) (Figure Not Available) . Interestingly, the phenotype of central obesity and decreased lean body mass is shared by patients with Cushing's syndrome and some patients with the combined diagnosis of melancholic depression or chronic anxiety disorder and the metabolic syndrome X (visceral obesity, insulin resistance, dyslipidemia, hypertension) or ''pseudo-Cushing's syndrome.'' [3] [30] [67]
Because increased gluconeogenesis is a characteristic feature of the stress response and because glucocorticoids induce insulin resistance, activation of the HPA axis may contribute to the poor control of diabetic patients during periods of emotional stress (Fig. 7) (Figure Not Available) , or concurrently with inflammatory and other diseases. Indeed, mild chronic activation of the HPA axis was recently demonstrated in diabetic patients under moderate or poor glycemic control. Glucocorticoid-induced, progressively increasing visceral adiposity directly causes further insulin resistance and deterioration of glycemic control in patients with diabetes mellitus. Chronic activation of the stress system in this disorder participates in a vicious cycle of increasing hyperglycemia, hypercholesterolemia, and insulin needs.[16]
An efficient stress response is appropriately triggered, reaches an amplitude commensurate with its intensity, and is turned off shortly after stress is over.[34] The widespread effects of stress on the body are ordinarily transient and tolerable. Because of the critical influence of the stress response on the entire body, the smallest dysfunction can affect virtually any organ or body system.[35] The vulnerability of a particular body system to stress varies from one individual to another. Likewise, severe or prolonged stress may cause anxiety or depression in some individuals, sexual insufficiency in others, or irritable bowel syndrome or peptic ulcer in a third group.[22] [69] [94] Vulnerability to any of these syndromes is determined by the genetic and constitutional make-up of the individual and may be ameliorated or accentuated by environmental factors, particularly at critical periods of development.
The time-limited nature of the stress response renders its accompanying antireproductive, antigrowth, catabolic, and immunosuppressive effects temporarily beneficial rather than damaging. In contrast, chronicity of stress system activation may lead to a pathologic syndrome. Because CRH coordinates behavioral, neuroendocrine, and autonomic adaptation during stressful situations, increased and prolonged production of CRH is likely to contribute to the pathogenesis and the manifestations of this syndrome.[16]
The best example of a chronic hyperactivation of the stress system is manifested in melancholic depression[38] (Fig. 8) (Figure Not Available) . This syndrome represents a prototypic example of dysregulated activation of the generalized stress response, leading to dysphoric hyperarousal, chronic activation of the HPA axis and locus coeruleus-norepinephrine system, and relative immunosuppression.[36] Indeed, cortisol excretion is increased and plasma ACTH response to exogenous CRH decreased. These findings suggest that, in depression, hypersecretion of CRH occurs, which may participate in the initiation or perpetuation of a vicious cycle. Recently, depressed patients were found on autopsy to have markedly increased numbers of PVN CRH and AVP neurons. In two more recent imaging studies, depressed patients were found to have marked hippocampal atrophy and a decreased size and metabolic activity of the subgenual medial prefrontal cortex. Whether any of these changes are genetically determined, environmentally induced, or both is unclear. Each and all of them could result in a hyperactive stress system and melancholic depression.[34]
Owing to chronically or recurrently hyperactive stress, patients with melancholic depression may sustain several severe somatic sequelae, such as osteoporosis, varying degrees and patterns of the metabolic syndrome X, and innate and T helper 1-directed immunosuppression. A study of the mineral bone density of young women with recurrent depression revealed the presence of clinically significant loss of bone mineral density.[79] Plasma osteocalcin concentrations and urinary pyrinidinium crosslinks were suppressed, revealing ''low turnover'' osteoporosis, similar to that observed in patients with Cushing's syndrome.[77]
Over the years, numerous patients with melancholic depression, hypercortisolism, and obesity have been referred to the authors to rule out the diagnosis of Cushing's syndrome.[36] [37] [59] The authors have devised a combined dexamethasone-ovine CRH test, which differentiates patients with pseudo-Cushing's syndrome from patients with bona fide Cushing's syndrome. The former group are thought to have depression-induced metabolic syndrome X, with some or all of its manifestations. In testing performed by the authors, nondepressed obese subjects with or without manifestations of the metabolic syndrome X have normal cortisol production indices.
In addition to osteoporosis and metabolic syndrome X, patients with melancholic depression sustain varying degrees of atherosclerosis, cardiovascular disease, and innate and T-helper 1-directed immunosuppression and certain infectious and neoplastic diseases. When not treated, these patients have a compromised life expectancy curtailed by 15 to 20 years after excluding suicides, the prevalence of which is increased in this group.[16] [34]
In addition to melancholic depression, a spectrum of other conditions may be associated with increased and prolonged activation of the HPA axis, including anorexia nervosa with or without malnutrition, obsessive-compulsive disorder, panic anxiety, excessive exercising, chronic active alcoholism, alcohol and narcotic withdrawal, poorly controlled diabetes mellitus type 1 and 2, childhood sexual abuse, and hyperthyroidism.[19] [32] [37]
Neuropeptide Y also seems to have an important role in the pathogenesis of stress-related illnesses.[68] Levels of NPY are decreased in the cerebrospinal fluid of patients with major depression,[110] and the chromatographic profiles of immunoreactive material differ between patients and controls.[43] [83] Marked reductions of tissue levels of NPY are also reported in suicide victims.[114]
Tricyclic antidepressant treatment is associated with increased levels of NPY in the rat brain.[113] Electroconvulsive shocks increase tissue levels of NPY in frontal cortical and hippocampal areas.[70] Lithium has been found to enhance NPY gene expression.[51][109] Olfactory bulbectomy has been suggested as an animal model of depression, and bulbectomized rats kill mice (''muricidal behavior''). This behavior is inhibited by injecting norepinephrine into the central nucleus of the amygdala. The inhibition of muricidal behavior by norepinephrine is markedly potentiated by NPY.[55]
Anorexia nervosa and malnutrition are characterized by increased levels of cerebrospinal fluid NPY,[56] which could provide an explanation why the HPA axis in these subjects is activated, whereas the locus coeruleus-norepinephrine system is markedly hypoactive.[63] Glucocorticoids, by stimulating NPY and inhibiting the PVN CRH and the locus coeruleus-norepinephrine systems, contribute to the hyperphagia and obesity observed in Cushing's syndrome.[19] A defect in the leptin system, such as seen in the Zucker rat, is associated with hypersecretion of NPY and glucocorticoids and a hypofunctional locus coeruleus-norepinephrine system, all leading to profound obesity.[16]
Psychosocial dwarfism is a term describing severe childhood or adolescent short stature with or without delayed puberty owing to emotional deprivation or abuse.[19] Decreased growth hormone secretion that is reversible after separation of the child from the responsible environment is a characteristic finding in this condition, which is also associated with a variety of behavioral abnormalities, such as depression and pica and other bizarre eating behaviors. In addition to low growth hormone secretion, these patients have a dysfunctional thyroid axis, resembling the ''euthyroid sick'' syndrome. Although little is known about the HPA axis in children with this condition, it is suspected that at least its central component is chronically activated, which would explain the other endocrine and growth abnormalities.[18]
Chronic stress in early life is associated with a high prevalence of peptic ulceration and irritable bowel syndrome later in adulthood. Both disorders seem to be interrelated and frequently comorbid with affective and anxiety disorders[12][31] (see Fig. 3 ). Recent evidence suggests that such conditions are mediated by CRH neuronal activity and, specifically, through its type-1 receptor. Administration of a nonpeptide CRH-R1 antagonist to stressed rats prevents the development of both disease indices.[41E]
Corticotropin-releasing hormone released in the gastrointestinal mucosa from immune cells or enterochromaffin cells may have a role in the modulation of rectal afferent function because it decreases the thresholds and increases the intensity for the sensation of discomfort in response to distention.[64] These findings are consistent with a dual effect of CRH on afferent pathways mediating the perception of aversive rectal sensations in humans. CRH also mediates the increase in locus coeruleus spontaneous discharge during colonic distension in rats. Activation of the locus coeruleus-noradrenergic system during colon distention has been suggested to serve as a cognitive limb of the parasympathetic system and to have a role in disorders characterized by comorbidity of intestinal and psychiatric symptoms, such as irritable bowel syndrome. On the efferent side, CRH acts in the locus coeruleus to induce a long-lasting stimulation of colonic transit and bowel discharge.[72][106]
Hypoactivation of the stress system rather than sustained activation, in which chronically reduced secretion of CRH may result in pathologic hypoarousal, characterizes another group of states. Patients with atypical seasonal depression and the chronic fatigue syndrome fall in this category. In the depressive (winter) state of the former and in the period of fatigue in the latter, there is decreased activity of the HPA axis. Similarly, patients with fibromyalgia have decreased urinary free cortisol excretion and frequently complain of fatigue. Hypothyroid patients also have clear evidence of CRH hyposecretion. One of the major manifestations of hypothyroidism is depression of the ''atypical'' type. [34]
Withdrawal from smoking has been associated with decreased cortisol and catecholamine secretion. Decreased CRH secretion in the early period of nicotine abstinence could explain the hyperphagia, hypometabolism, and weight gain frequently observed in these patients. In Cushing's syndrome, the clinical presentation of atypical depression, hyperphagia and weight gain, and fatigue and anergia is consistent with suppression of the CRH neuron in some sites by the associated hypercortisolism. The period after cure of hypercortisolism, the postpartum period, and periods following cessation of chronic stress are also associated with atypical depression, suppressed PVN CRH secretion, and decreased HPA axis activity.[18]
Theoretically, an excessive HPA axis response to inflammatory stimuli would mimic the stress or hypercortisolemic state and would lead to increased susceptibility of the individual to a host of infectious agents or tumors as a result of T-helper-1 suppression but enhanced resistance to autoimmune/inflammatory diseases. In contrast, a defective HPA axis response to such stimuli would reproduce the glucocorticoid-deficient state and lead to a relative resistance to infections and neoplastic diseases but increased susceptibility to T-helper-1-mediated autoimmune/inflammatory diseases, such as Hashimoto thyroiditis or rheumatoid arthritis.[27]
Indeed, such properties were unraveled in an interesting pair of near-histocompatible, highly inbred rat strains, the Fischer and Lewis rats, respectively, for their resistance or susceptibility to inflammatory disease.[21] [48] An increasing body of evidence suggests that patients with rheumatoid arthritis have an increased incidence of atypical depression, as well as a mild form of central hypocortisolism, because they have a paradoxically normal 24-hour cortisol excretion and blunted adrenal responses to surgical stress. Dysfunction of the HPA axis may actually have a role in the development or perpetuation of autoimmune disease, rather than being an epiphenomenon. The same rationale may explain the high incidence of autoimmune disease in the period after cure of hypercortisolism and the postpartum period, as well as in glucocorticoid unreplaced or underreplaced adrenal insufficiency.
Comprehending the mechanistics of the stress response and the increasingly serious sequelae of its dysregulation is pivotal to recognize and combat any abnormalities in the stress system. To overcome pathologic hyperactivity of the stress response, it is essential to protect juveniles from trauma and abuse. The more secure the environment, the less likely an individual will experience a stress-related illness. A secondary measure is training stress-prone patients to improve their coping skills, minimizing their reactivity to future stress. In-depth understanding of the neurocircuitry of stress has provided novel tools to manage hyperactivity of the stress system.
Hundreds of original articles and numerous laboratories have repeatedly implicated CRH in enhancing the organism's sensitivity to nocuous stimuli and in mobilizing almost the entire cascade of the stress response. By virtue of its broad interactions with the endocrine and autonomic systems, CRH virtually influences every cell in the body. Hyperactivity of CRH is a serious condition that is likely to underlie the pathophysiology of melancholic depression, anxiety, psychosexual disorders, diabetes mellitus, and functional gastrointestinal disorders.
One of the most revolutionary progresses in medicine is the introduction of nonpeptide CRH receptor antagonists to target directly the stress system in the brain. Although still in phase 1 trials, preclinical findings from the authors' and others' laboratories strongly indicate the efficacy and low side-effect profile of CRH-R1 antagonists against mental and physical disorders that are exacerbated or precipitated by stress. Such agents are likely to be helpful in treating a wide spectrum of psychiatric disorders, such as melancholic depression, anorexia nervosa, obsessive-compulsive disorder, and withdrawal from certain narcotic agents. Several medical illnesses will probably benefit from such therapies as soon as these prove to be clinically safe and pharmacologically efficacious.
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