Am J Psychiatry 161:195-216, February 2004
© 2004 American Psychiatric Association
Psychobiological Mechanisms of Resilience and Vulnerability: Implications for Successful Adaptation to Extreme Stress
Dennis S. Charney, M.D.
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Abstract
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OBJECTIVE: Most research on the effects of severe psychological stress has focused on stress-related psychopathology. Here, the author develops psychobiological models of resilience to extreme stress. METHOD: An integrative model of resilience and vulnerability that encompasses the neurochemical response patterns to acute stress and the neural mechanisms mediating reward, fear conditioning and extinction, and social behavior is proposed. RESULTS: Eleven possible neurochemical, neuropeptide, and hormonal mediators of the psychobiological response to extreme stress were identified and related to resilience or vulnerability. The neural mechanisms of reward and motivation (hedonia, optimism, and learned helpfulness), fear responsiveness (effective behaviors despite fear), and adaptive social behavior (altruism, bonding, and teamwork) were found to be relevant to the character traits associated with resilience. CONCLUSIONS: The opportunity now exists to bring to bear the full power of advances in our understanding of the neurobiological basis of behavior to facilitate the discoveries needed to predict, prevent, and treat stress-related psychopathology.
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Introduction
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The adaptive physiological response to acute stress involves a process, initially referred to as allostasis by Sterling and Eyer (1), in which the internal milieu varies to meet perceived and anticipated demand. McEwen (2) extended this definition to include the concept of a set point that changes because of the process of maintaining homeostasis (2). The responses to severe stress that promote survival in the context of a life-threatening situation may be adaptive in the short run. However, if recovery from the acute event is not accompanied by an adequate homeostatic response to terminate the acute adaptive response of stress mediators, the deleterious effects on psychological and physiological function, termed the "allostatic load," occur. The allostatic load is the burden borne by a brain and body adapting to challenges, both physiological and psychological. The concepts of allostasis and allostatic load link the protective and survival values of the acute response to stress to the adverse consequences that result if the acute response persists (3).
Much of the research on allostasis and allostatic load has focused on the negative effects of physiological stress on the brain and body. The present discussion will consider allostasis and allostatic load from the perspective of the effects of extreme psychological stress on the complex regulation of emotion by the brain and the consequences of such changes on human psychological resilience on one hand, and vulnerability to psychopathology on the other. Most of the neurobiological research on the consequences of severe psychological stress has focused on psychopathological responses that relate to stress-related disorders, such as posttraumatic stress disorder (PTSD) and major depression. Surprisingly, there has been little attention directed toward the question of which neurobiological responses are related to resilience to psychological stress in general and to specific forms of psychopathology.
Identification of responses that relate to psychobiological allostasis and reduced psychobiological allostatic load may provide clues toward discovering improved methods to prevent and treat disorders such as PTSD and major depression. For example, which aspects of the acute neurochemical response to traumatic stress promote behaviors that facilitate an effective survival reaction and may account for instances of highly effective action while experiencing fear? What psychobiological responses serve to maintain neural systems regulating reward and motivation in the face of an unrewarding environment? What alterations in neural systems regulating fear conditioning and extinction serve to maintain low levels of anxiety, despite an uncontrollable stress environment? Which changes in the neural systems involved in learning and memory can affect the encoding, consolidation, reconsolidation, and retrieval of memories of trauma so that normal psychological function can be maintained and re-experiencing symptoms minimized? How can neural systems regulating social behavior respond to persistent abuse and neglect to avoid a sense of hopelessness and interpersonal withdrawal? The answers to such questions may provide a greater understanding of why some individuals are able to cope with extreme stress with minimal psychopathological consequences.
A number of neurotransmitters, neuropeptides, and hormones have been linked to the acute psychobiological response to stress and the long-term psychiatric outcome. The roles of those neurotransmitters, neuropeptides, and hormones that have been shown to be significantly altered by psychological stress, have important functional interactions, and mediate the neural mechanisms and neural circuits relevant to the regulation of reward, fear conditioning, and social behavior will be reviewed. An attempt will be made to identify a putative neurochemical profile that characterizes psychobiological resilience and has predictive value regarding successful adaptation to extreme stress.
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Cortisol and Dehydroepiandrosterone
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There is consistent evidence that many forms of psychological stress increase the synthesis and release of cortisol. Cortisol serves to mobilize and replenish energy stores; it contributes to increased arousal, vigilance, focused attention, and memory formation; inhibition of the growth and reproductive system; and containment of the immune response. Cortisol has important regulatory effects on the hippocampus, amygdala, and prefrontal cortex (4). Glucocorticoids can enhance amygdala activity, increase corticotropin-releasing hormone (CRH) mRNA concentrations in the central nucleus of the amygdala (5–7), increase the effects of CRH on conditioned fear (8), and facilitate the encoding of emotion-related memory (9). Adrenal steroids such as cortisol have biphasic effects on hippocampal excitability and cognitive function and memory (10). These effects may contribute to adaptive alterations in behaviors induced by cortisol during the acute response to stress.
It is key, however, that the stress-induced increase in cortisol ultimately be constrained through an elaborate negative feedback system involving glucocorticoid and mineral corticoid receptors. Excessive and sustained cortisol secretion can have serious adverse effects, including hypertension, osteoporosis, immunosuppression, insulin resistance, dyslipidemia, dyscoagulation, and, ultimately, atherosclerosis and cardiovascular disease (11).
Another adrenal steroid released under stress is dehydroepiandrosterone (DHEA). DHEA is secreted episodically and synchronously with cortisol in response to fluctuating ACTH levels (12). DHEA has been shown to have antiglucocorticoid and antiglutamatergic activity in several tissues, including the brain (13), mediated by complicated mechanisms distinct from classical glucocorticoid receptor antagonism. Peripherally produced DHEA is thought to be a major source of brain DHEA. Within the brain, regionally specific metabolism of DHEA may ultimately control the nature of DHEA’s effects on cognition and behavior (14). For instance, 7-hydroxylated metabolites of DHEA in the hippocampus interfere with the normal uptake of activated glucocorticoid receptors (15) and may confer neuroprotection (16, 17). DHEA also restores cortisol-induced suppression of long-term potentiation in hippocampal neurons (18).
A negative correlation between DHEA reactivity to adrenal activation and the severity of PTSD has been reported, suggesting that enhanced DHEA release in response to prolonged stress may be protective in persons with PTSD (unpublished work by Rasmusson et al.). This is consistent with recent observations in a study of elite special operations soldiers that revealed negative correlations between ratios of DHEA to cortisol and dissociation during prolonged and extreme training stress and between DHEA and DHEA-S ("S" stands for sulfate) levels in the recovery period and better overall performance (unpublished work by Morgan et al.). Other evidence that suggests that DHEA promotes psychological resilience includes several studies reporting negative associations between plasma DHEA levels and depressive symptoms and the antidepressant effects of DHEA (19–22). Aside from the antiglucocorticoid actions of DHEA, effects on  -aminobutyric acid (GABA)A receptors (23) and N-methyl-D-aspartic acid (NMDA)-based neurotransmission (24) may be involved in the behavioral effects of DHEA.
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CRH
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CRH is one of the most important mediators of the stress response, coordinating the adaptive behavioral and physiological changes that occur during stress (25). Release of CRH from the hypothalamus into the hypothalamic-pituitary portal circulation occurs in response to stress, resulting in activation of the hypothalamic-pituitary-adrenal (HPA) axis and the increased release of cortisol and DHEA. Equally important are the extrahypothalamic effects of CRH. CRH-containing neurons are located throughout the brain, including the prefrontal and cingulate cortices, the central nucleus of the amygdala, the bed nucleus of the stria terminalis, the nucleus accumbens, the periaqueductal gray matter, and the brainstem nuclei, such as the major norepinephrine-containing nucleus, the locus coeruleus, and the serotonin (5-HT) nuclei in the dorsal and median raphe (26).
Increased activity of amygdala CRH neurons activates fear-related behaviors, while cortical CRH may reduce reward expectation. CRH also inhibits a variety of neurovegetative functions, such as food intake, sexual activity, and endocrine programs for growth and reproduction. It appears that early-life stress can produce long-term elevation of brain CRH activity and that individual response to heightened CRH function may depend upon the social environment, past trauma history, and behavioral dominance (27). Persistent elevation of hypothalamic and extrahypothalamic CRH contributes mightily to the psychobiological allostatic load. Increased CSF levels of CRH have been linked to PTSD and major depression (28–30). Psychobiological resilience may be related to an ability to restrain the initial CRH response to acute stress.
Both CRH-1 and CRH-2 receptors are found in the pituitary and throughout the neocortex (especially in the prefrontal, cingulate, striate, and insular cortices), the amygdala, and the hippocampal formation in the primate brain. The presence of CRH-1 (but not CRH-2) receptors within the locus coeruleus, the nucleus of the solitary tract, the thalamus, the striatum, CRH-2 (but not CRH-1) receptors in the choroid plexus, certain hypothalamic nuclei, the nucleus prepositus, and the bed nucleus of the stria terminalis suggests that each receptor subtype has distinct roles within the primate brain (31).
CRH-1-deficient mice display decreased anxiety-like behavior and an impaired stress response (32). In contrast, CRH-2-deficient mice display increased anxiety-like behavior and are hypersensitive to stress (33, 34). Thus, evidence exists in favor of opposite functional roles for the two known CRH receptors; activation of CRH-1 receptors may be responsible for increased anxiety-like responses, and stimulation of CRH-2 may produce anxiolytic-like responses. Regulation of the relative contribution of the two CRH receptor subtypes to brain CSF pathways may be essential to coordinating psychological and physiological responses to stressors (32). Thus far, it has not been possible to evaluate CRH-1 and CRH-2 receptors in living human subjects, although efforts are ongoing to develop CRH receptor positron emission tomography ligands.
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Locus Coeruleus-Norepinephrine System
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Stress activates the locus coeruleus, which results in increased norepinephrine release in projection sites of the locus coeruleus, including the amygdala, the prefrontal cortex, and the hippocampus. The locus coeruleus is activated by a variety of stressors, both intrinsic (hypoglycemia, decreased blood volume, decreased blood pressure, altered thermoregulation, and distention of the colon and bladder) and extrinsic (environmental stress or threat) to the animal. Such activation is adaptive to survival from a life-threatening situation and serves as a general alarm function. Activation of the locus coeruleus also contributes to the sympathetic nervous system and HPA axis stimulation. Coincidentally, activation of the locus coeruleus inhibits parasympathetic outflow and neurovegetative function, including eating and sleep. A high level of activation of the locus coeruleus-norepinephrine system inhibits function of the prefrontal cortex, thereby favoring instinctual responses over more complex cognition (35).
The ability of acute stress to coactivate the HPA and locus coeruleus-norepinephrine systems facilitates the encoding and relay of aversively charged emotional memories, beginning at the amygdala. The amygdala also inhibits the prefrontal cortex (such as the locus coeruleus) and stimulates hypothalamic CRH release and brainstem autonomic centers, resulting in increased activity of the HPA and locus coeruleus. These feedback loops among the prefrontal cortex, amygdala, hypothalamus, and brainstem noradrenergic neurons contain the elements for a sustained and powerful stress response (4). If unchecked, persistent hyperresponsiveness of the locus coeruleus-norepinephrine system will contribute to chronic anxiety, fear, intrusive memories, and an increased risk of hypertension and cardiovascular disease. In some patients with panic disorder, PTSD, and major depression, there is evidence of heightened locus coeruleus-norepinephrine activity (36–40).
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Neuropeptide Y
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Neuropeptide Y is a highly conserved 36 amino acid peptide, which is among the most abundant peptides found in the mammalian brain. There are five brain areas in which neurons containing neuropeptide Y are densely concentrated: the locus coeruleus (41), the paraventricular nucleus of the hypothalamus (42), septohippocampal neurons (43), the nucleus of the solitary tract, and the ventral lateral medulla (44). Moderate levels are found in the amygdala, hippocampus, cerebral cortex, basal ganglia, and thalamus (45).
Evidence suggesting the involvement of the amygdala in the anxiolytic effects of neuropeptide Y is robust and probably occurs by means of the neuropeptide Y-Y1 receptor (46–48). Microinjection of neuropeptide Y into the central nucleus of the amygdala reduces anxious behaviors. The up-regulation of amygdala neuropeptide Y mRNA levels after chronic stress suggests that neuropeptide Y may be involved in the adaptive responses to stress exposure (49). Neuropeptide Y may also be involved in the consolidation of fear memories; injection of neuropeptide Y into the amygdala impairs memory retention in a foot-shock avoidance paradigm (50). The anxiolytic effects of neuropeptide Y also involve the locus coeruleus, possibly by means of the neuropeptide Y-Y2 receptor. Neuropeptide Y reduces the firing of neurons in the locus coeruleus (51). Neuropeptide Y also has behaviorally relevant effects on the hippocampus. Transgenic rats with hippocampal neuropeptide Y overexpression have attenuated sensitivity to the behavioral consequences of stress and impaired spatial learning (52).
There are important functional interactions between neuropeptide Y and CRH (53, 54). Neuropeptide Y counteracts the anxiogenic effects of CRH, and a CRH antagonist blocks the anxiogenic effects of a neuropeptide Y-Y1 antagonist (55). Thus, it has been suggested that the balance between neuropeptide Y and CRH neurotransmission is important to the emotional responses to stress (54). In general, brain regions that express CRH and CRH receptors also contain neuropeptide Y and neuropeptide Y receptors, and the functional effects are often opposite (56), especially at the level of the locus coeruleus (57, 58), amygdala (59, 60), and the periaqueductal gray matter (61, 62).
These data suggest an important role for an up-regulated neuropeptide Y system in the psychobiology of resilience. Neuropeptide Y has counterregulatory effects on both the CRH and locus coeruleus-norepinephrine systems at brain sites that are important in the expression of anxiety, fear, and depression. Preliminary studies in special operations soldiers under extreme training stress indicate that high neuropeptide Y levels are associated with better performance (63). Patients with PTSD have been shown to have reduced plasma neuropeptide Y levels and a blunted yohimbine-induced neuropeptide Y increase (64). Additionally, low levels of neuropeptide Y have been found in depressed patients, and a variety of antidepressant drugs increase neuropeptide Y levels (65).
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Galanin
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Galanin is a peptide that, in humans, contains 30 amino acids. It has been demonstrated to be involved in a number of physiological and behavioral functions, including learning and memory, pain control, food intake, neuroendocrine control, cardiovascular regulation, and, most recently, anxiety (66).
Galanin is closely associated with ascending monoamine pathways. Approximately 80% of noradrenergic cells in the locus coeruleus co-express galanin. A dense galanin immunoreactive fiber system originating in the locus coeruleus innervates forebrain and midbrain structures, including the hippocampus, hypothalamus, amygdala, and prefrontal cortex (67–69). Neurophysiological studies have shown that galanin reduces the firing rate of the locus coeruleus, possibly by stimulating the galanin-1 receptor, which acts as an autoreceptor (70, 71).
Studies in rats have shown that galanin administered centrally modulates anxiety-related behaviors (72, 73). Galanin-overexpressing transgenic mice do not exhibit an anxiety-like phenotype when tested under baseline (nonchallenged) conditions. However, these mice are unresponsive to the anxiogenic effects of the alpha-2 receptor antagonist yohimbine. Consistent with this observation, galanin administered directly into the central nucleus of the amygdala blocked the anxiogenic effects of stress, which is associated with increased norepinephrine release in the central nucleus of the amygdala. Yohimbine increases galanin release in the central nucleus of the amygdala (74). Galanin administration and galanin overexpression in the hippocampus result in deficits in fear conditioning (75).
The mechanism by which galanin reduces norepinephrine release at locus coeruleus projections to the amygdala, hypothalamus, and prefrontal cortex may be a direct action of galanin on these brain regions by means of galanin-synthesizing neurons or by stimulating galanin receptors in these regions (71, 74). It is not known which galanin receptors are involved. Galanin-1 receptor mRNA levels are high in the amygdala, hypothalamus, and bed nucleus of the stria terminalis (76), and galanin-1 receptor-deficient mice show increased anxiety-like behavior (77).
These results suggest that the noradrenergic response to stress can recruit the release of galanin in the central nucleus of the amygdala and prefrontal cortex, which then buffers the anxiogenic effects of norepinephrine. Thus, the net behavioral response due to stress-induced noradrenergic hyperactivity may depend upon the balance between norepinephrine and neuropeptide Y and galanin neurotransmission. This hypothesis is consistent with evidence that release of neuropeptides preferentially occurs under conditions of high neurotransmitter activity (78, 79). To our knowledge, galanin function has not been studied in patients exposed to traumatic stress or patients with PTSD or major depression. Galanin and neuropeptide Y receptor agonists may be novel targets for the development of antianxiety drugs (71).
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Dopamine
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Uncontrollable stress activates dopamine release in the medial prefrontal cortex (80) and inhibits dopamine release in the nucleus accumbens (81, 82). Lesions of the pretraining and posttraining amygdala in a conditioned stress model block stress-induced dopamine metabolic activation in the medial prefrontal cortex, suggesting amygdala control of stress-induced dopamine activation and a role for integrating the behavioral and neuroendocrine components of the stress response (83). There is preclinical evidence that the susceptibility of the mesocortical dopamine system to stress activation may be in part genetically determined. It has been suggested that excessive mesocortical dopamine release by stressful events may represent a vulnerability to depression and favor helpless reactions through an inhibition of subcortical dopamine transmission (80, 82). These observations may be due to the effect of dopamine on reward mechanisms.
On the other hand, lesions of dopamine neurons in the medial prefrontal cortex delay extinction of the conditioned fear stress response (no effect on acquisition), indicating that prefrontal dopamine neurons are involved in facilitating extinction of the fear response. This suggests that reduced prefrontal cortical dopamine results in the preservation of fear produced by a conditioned stressor, a situation hypothesized to occur in PTSD (84). One way to reconcile these two sets of data is to suggest that there is an optimal range for stress-induced increases in cortical dopamine released in the medial prefrontal cortex to facilitate adaptive behavioral responses. Too much dopamine release in the medial prefrontal cortex produces cognitive impairment; an inhibition in dopamine activity in the nucleus accumbens results in abnormalities in motivation and reward mechanisms. Insufficient prefrontal cortical dopamine release delays extinction of conditioned fear. There has been little clinical research regarding dopamine function as it pertains to stress-related psychopathology. Several clinical investigations have reported increased urinary and plasma dopamine concentrations (85, 86) in PTSD. In contrast, reduced dopamine metabolism has been demonstrated in depressed patients (87).
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Serotonin
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Different types of acute stress result in increased 5-HT turnover in the prefrontal cortex, nucleus accumbens, amygdala, and lateral hypothalamus (88). Serotonin release may have both anxiogenic and anxiolytic effects, depending on the region of the forebrain involved and the receptor subtype activated. For example, anxiogenic effects are mediated by means of the 5-HT2A receptor, whereas stimulation of 5-HT1A receptors are anxiolytic and may even relate to adaptive responses to aversive events (89).
Understanding the function of the 5-HT1A receptor is probably most pertinent to the current discussion. The 5-HT1A receptors are found in the superficial cortical layers, the hippocampus, the amygdala, and the raphe nucleus (primarily presynaptic) (90, 91). The behavioral phenotype of 5-HT1A knockout mice includes increases in anxiety-like behaviors (92, 93). These behaviors are mediated by postsynaptic 5-HT1A receptors in the hippocampus, amygdala, and cortex (94). Of great interest is the recent finding that embryonic and early postnatal shutdown of expression of 5-HT1A receptors produces an anxiety phenotype that cannot be rescued with restoration of 5-HT1A receptors. However, when 5-HT1A receptor expression is reduced in adulthood and then reinstated, the anxiety phenotype is no longer present. These results suggest that altered function of 5-HT1A receptors early in life can produce long-term abnormalities in the regulation of anxiety behaviors (94).
Postsynaptic 5-HT1A receptor gene expression is under tonic inhibition by adrenal steroids such as in the hippocampus, apparently mostly by means of activation of mineral corticoid receptors. 5-HT1A receptor density and mRNA levels decrease in response to stress, which is prevented by adrenalectomy (95).
There may also be important functional interactions between 5-HT1A and benzodiazepine receptors. In one study of 5-HT1A knockout mice, a down-regulation of benzodiazepine GABA  1 and 2 receptor subunits, as well as benzodiazepine-resistant anxiety in the elevated-plus maze was reported (96). However, a subsequent study did not replicate these results using mice with a different genetic background (97), raising the possibility that genetic background can affect functional interplay between 5-HT1A and benzodiazepine systems.
These results suggest a scenario in which early-life stress increases CRH and cortisol levels, which, in turn, down-regulate 5-HT1A receptors, resulting in a lower threshold for anxiogenic stressful life events. Alternatively, 5-HT1A receptors may be decreased on a genetic basis. The density of 5-HT1A receptors is reduced in depressed patients when they are depressed as well as in remission (98). It has been recently demonstrated that 5-HT1A receptor density is also decreased in patients with panic disorder (99). Examination of 5-HT1A receptor density in patients with anxiety disorders is indicated.
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Benzodiazepine Receptors
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Animals exposed to chronic inescapable stress develop behaviors that are consistent with excessive fear and anxiety, such as increased fearfulness, increased defecation, and avoidance of novel situations (e.g., an open field). Exposure to inescapable stressors produce decreases in benzodiazepine receptor binding in the cortex, with some studies showing a decrease in the hippocampus (100, 101). Exposure to stress has no effects on benzodiazepine receptor binding in the pons, striatum, thalamus, cerebellum, midbrain, or occipital cortex. These data support a role for alterations in benzodiazepine binding in anxiety, with a specific decrease in the frontal cortex and, although not as consistently, a decrease in the hippocampus (101).
Neuroimaging studies reveal reduced cortical and subcortical benzodiazepine receptor binding in patients with PTSD and panic disorder (102–104). The findings could be related to a down-regulation of benzodiazepine receptor binding after exposure to stress. Other possible explanations are that stress results in changes in receptor affinity, changes in an endogenous benzodiazepine ligand (the existence of which is controversial), and stress-related alterations in GABAergic transmission or neurosteroids that affect benzodiazepine receptor binding. A preexisting low level of benzodiazepine receptor density may be a genetic risk factor for the development of stress-related anxiety disorders.
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Gonadal Steroids
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Testosterone
Testosterone has been among the most studied of all hormones in terms of its relationships to specific behaviors. Aggression is the aspect of human behavior most often linked to testosterone concentrations (105). Preclinical studies consistently show that low levels of testosterone are associated with submissive behavior. In mandrils and squirrel monkeys, social rank correlates with testosterone levels (105, 106). In human subjects, the personal experience of success, as well as the feeling of dominance in a competitive situation, is associated with higher testosterone levels (107, 108). Increased levels of testosterone have been found in male prison inmates with frequent episodes of violent behavior (109–111). Psychological stress is associated with decreases in testosterone levels. For example, elite soldiers participating in a physically and psychologically stressful training exercise show a lowering of their testosterone levels (63).
The mechanism by which testosterone is reduced by physical and psychological stress remains to be elucidated. It is unclear whether the decrease in testosterone from exposure to mental stress is caused by decreased leuteinizing hormone-releasing hormone (LH-RH) synthesis at the hypothalamus or leuteinizing hormone (LH) secretion in the pituitary (105). Perhaps a more likely mechanism involves a recently identified hypothalamic-testicular pathway that is independent of the pituitary but travels through the spinal cord. This pathway appears to mediate the effect of CRH to decrease testosterone levels. Thus, hypothalamic increases in CRH produced by psychological stress may be associated with decreased testosterone by stimulating the neural pathway that interferes with Leydig cell function independently of the pituitary. It is important to establish the relative role of the LH-RH/LH axis and the hypothalamic testicular axis in modulating the influence of specific stressors on testosterone release (112).
There is a recent report of reduced CSF testosterone levels in PTSD patients that was negatively correlated with CSF CRH concentrations (113). There was no correlation between plasma and CSF testosterone levels (113). The data from studies measuring plasma testosterone levels in PTSD patients are mixed (114).
Depressed men have been found to have decreased serum or plasma testosterone in some studies (115), but not all, because of confounding factors. Hypogonadal men often experience depressive symptoms, which are improved by testosterone-replacement therapy (116). Clinical trials of depressed men with decreased testosterone have produced contradictory results. However, a recent placebo-controlled study (115) found testosterone gel to be effective for men with treatment-resistant depression and low testosterone levels when added to an existing antidepressant regimen. Testosterone administration may be helpful for patients with low testosterone secondary to chronic severe psychological stress.
Estrogen
There is abundant preclinical and clinical literature demonstrating consistent gender differences in stress responsiveness (117). Most of the work focused on HPA responses to stressors. Female rats consistently show greater increases in corticosterone and ACTH in response to acute and chronic stressors. These differences have generally been attributed to the activational effects of gonadal steroids on elements of the HPA axis in females (118). Several studies suggest that estradiol plays a role in enhanced stress responses in female rats, based upon increased HPA axis responses to stress when ovariectomized rats are treated with estradiol (119). A possible mechanism for these findings is that estrogen (as well as progesterone) produces a relative resistance to glucocorticoid feedback (120).
However, a recent investigation by Young and colleagues, studying the effects of estrogen antagonists and physiological doses of estradiol, found that estradiol reduced the ACTH response to restraint stress in female rats (118). The estrogen antagonists had the opposite effect. These data suggest that physiological doses of estradiol are inhibitory to stress responsiveness and that blocking estradiol on gonadally intact, normally cycling female rats leads to exaggerated stress responsiveness. The contrast with prior studies seems to relate to the dosage of estradiol and the duration of administration. Considered together, the studies indicate that short-term exposure to low doses of estrogen can suppress HPA axis responses to stress but higher doses and more prolonged treatment enhances HPA axis responses (117, 118). The mechanism underlying these effects could be due to enhanced negative feedback or decreases in the stimulatory aspects of the system, related to either CRH or ACTH. This remains to be elucidated, since studies examining the effects of estradiol on mineral corticoid receptor and glucocorticoid receptor binding and mRNA expression and on CRH have not yielded consistent results, perhaps due to variability in doses and duration of treatment regimens.
Studies in human populations suggest that female subjects respond with greater HPA activation to stressors involving interpersonal concerns (social rejection) and male subjects to achievement-oriented stressors (117). The role of estrogen in these differential responses remains to be studied. Estrogen has been shown to blunt HPA axis responses to psychological stress in postmenopausal women (121, 122) and to blunt the ACTH response to CRH in postmenopausal women with high levels of body fat. In addition, 8 weeks of estrogen supplementation to perimenopausal women blunted systolic and diastolic blood pressure, cortisol, ACTH, plasma epinephrine and norepinephrine, and norepinephrine responses of the entire body to stress (120).
Although the mechanisms responsible for the effect of estrogen on glucocorticoid levels are not fully defined, it appears that it acts by means of ACTH and thus the pituitary or hypothalamus rather than directly on the adrenal gland. This is consistent with evidence obtained from women with hypothalamic amenorrhea, in whom a blunted response to CRH administration and increased cortisol levels were observed (123). These effects could be explained by a direct action of estrogen on CRH gene expression or glucocorticoid receptor numbers or function (124).
The mechanisms by which estrogens affect catecholamine levels are also uncertain. The effects of estrogen may be due to actions on the adrenal gland or central or peripheral neuronal pathways. Neuronal pathways seem more likely (125), although several different mechanisms may be involved, including effects on 1-noradrenergic (126) and ß-noradrenergic (127) receptors and modulation of norepinephrine release. Estrogen has also been shown to up-regulate the GABAA benzodiazepine receptor (128).
The effects of estrogen on mood and anxiety may be mediated in part by the serotonin system (129). Estrogen has complex effects on functioning of the serotonin system, including increased tryptophan hydroxylase gene and protein expression (130), decreased expression of the serotonin transporter (131), and increased 5-HT2A binding (132). Perhaps most important are studies relevant to the 5-HT1A receptor. Estrogen in both rats and monkeys decreases 5-HT1A in RNA and 5-HT1A binding in both presynaptic (dorsal raphe) and postsynaptic sites (133). Estrogen also decreases the inhibitory G proteins involved in intracellular signal transduction mediated by the 5-HT1A receptor (134, 135).
Women appear to be more sensitive to the effects of traumatic stress. One survey found that 31% of women and 19% of men develop PTSD when exposed to major trauma (136). However, the role of estrogen in the development of PTSD has not been investigated. Based upon these data, short-term increases in estrogen after exposure to stress might be beneficial because of its ability to blunt the HPA axis and noradrenergic response to stress. However long-term stress-related elevation in estrogen might be detrimental because of estrogen-induced decreases in 5-HT1A receptor numbers and function.
Resilience and Vulnerability to Stress
The last section identified 11 possible mediators of the psychobiological response to extreme stress and how each may contribute, alone or through functional interactions, to resilience or vulnerability (Table 1 and Figure 1). In the beginning of this article, the concept of allostatic load was introduced as a measure of the cumulative physiological burden borne by the body from attempts to adapt to stressors and strains of life’s demands (137). McEwen and Stellar (3) hypothesized that the cumulative impact on health risk from modest dysregulations in multiple systems can be substantial, even if they individually have minimal and insignificant health effects. Thus, they defined allostatic load as a cumulative measure of physiological dysregulation over multiple systems (3).
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Figure 1. Neurochemical Response Patterns to Acute Stressa
aThis figure illustrates some of the key brain structures involved in the neurochemical response patterns following acute psychological stress. The functional interactions among the different neurotransmitters, neuropeptides, and hormones are emphasized. It is apparent the functional status of brain regions such as the amygdala (neuropeptide Y, galanin, corticotropin-releasing hormone [CRH], cortisol, and norepinephrine), hippocampus (cortisol and norepinephrine), locus coeruleus (neuropeptide Y, galanin, and CRH), and prefrontal cortex (dopamine, norepinephrine, galanin, and cortisol) will depend upon the balance among multiple inhibitory and excitatory neurochemical inputs. It is also noteworthy that functional effects may vary depending on the brain region. Cortisol increases CRH concentrations in the amygdala and decreases concentrations in the paraventricular nucleus of the hypothalamus. As described in the text, these neurochemical response patterns may relate to resilience and vulnerability to the effects of extreme psychological stress.
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The concept of allostatic load has proven to be useful as a predictor of functional decline in elderly men and women. Seeman and colleagues (138) developed a measure of allostatic load based on 10 markers reflecting levels of physiological activity across a range of important regulatory systems, which individually have been linked to disease based upon data from a longitudinal community-based study of successful aging (138). The markers were the following:
- Twelve-hour overnight urinary cortisol excretion
- Twelve-hour overnight urinary excretion of norepinephrine
- Twelve-hour overnight urinary excretion of epinephrine
- Serum DHEA-S level
- Average systolic blood pressure
- Average diastolic blood pressure
- Ratio of waist-hip circumference
- Serum high-density lipid (HDL) cholesterol
- Ratio of total cholesterol to HDL cholesterol
- Blood-glycosylated hemoglobin
For each of the 10 markers, the subjects were classified into quartiles based upon the distribution of scores in the baseline cohort. Allostatic load was measured by summing the number of parameters for which the subject fell into the highest-risk quartile (top quartile for all markers except HDL cholesterol and DHEA-S, for which the lowest quartile corresponds to the highest risk). In two follow-up studies encompassing 2.5 and 7 years, none of the 10 markers of allostatic load exhibited significant associations on their own with health outcomes. However, the summaried measure of allostatic load was found to be significantly associated with four major health outcomes: 1) new cardiovascular events, 2) a decline in cognitive functioning, 3) a decline in physical functioning, and 4) mortality. Thus, these data are consistent with the hypothesis that although modest abnormalities in a single physiological system may not be predictive of poor health outcome, the cumulative effect of multiple abnormalities in the physiological system is prognostic of poor physical health (11, 138).
The allostatic load concept has not been used to investigate neurobiological risk factors related to psychopathology. Perhaps an analogous approach that involves the identification of a group of biological markers that will relate to psychobiological allostasis and psychobiological allostatic load and, consequently, to resilience and vulnerability to the effects of extreme psychobiological stress will be fruitful. It is in this context that this review of the neurochemical response patterns to stress can provide a framework for developing a measure for psychobiological allostatic load. The finding that many of these measures have important functional interactions is supportive of the concept of developing a more integrative measure. One prediction is that individuals in the highest quartile for measures of HPA axis, CRH, locus coeruleus-norepinephrine, dopamine, and estrogen activity and the lowest quartile for DHEA, neuropeptide Y, galanin, testosterone, and 5-HT1A receptor and benzodiazepine receptor function will have the highest index for psychobiological allostatic load and an increased risk for psychopathology after exposure to stress. It is possible that psychobiological allostatic load will relate to vulnerability to the effects of chronic, mild, intermittent stressors as well as extreme psychological trauma. In contrast, a resilient profile will be characterized by individuals in the highest quartile for measures of DHEA, neuropeptide Y, galanin, testosterone, and 5-HT1A receptor and benzodiazepine receptor function and the lowest quartile for HPA axis, CRH, and locus coeruleus-norepinephrine activity (Table 1). The mediators of the stress response identified in this review are not meant to be an exhaustive or definitive list. For example, glutamate and neurotrophic factors, such as brain-derived neurotrophic factor, and neuropeptides, such as substance P and cholecystokinin, could have been included. Longitudinal community-based surveys of successful adaptation to extreme stress should be considered to determine if markers such as these or others can be used to develop a measure of psychobiological allostatic load that will be of predictive value.
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Reward, Fear Conditioning, and Social Behavior
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Abstract
Introduction