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Glucocorticoid Feedback Resistance
Glucocorticoid Feedback Resistance E. Ronald De Kloet, Erno Vreugdenhil, Melly S. Oitzl, and Marian Joels
Glucocorticoid feedback resistance can be inherited or locally acquired. The implications of these two forms of resistance for disease are strikingly different. The inherited form is characten”zed by enhanced adrenocortical function and hypercorticisrn to compensate for a generalized deficit in the glucocorticoid receptor gene, but these individuals lack symptoms of Cushing’s syndrome. By contrast, resistance acquired at the level of the hypothalamic corticotropin-releasing hormone (CRH) neurons is linked to hypercorticism, which is not compensatory but overexposes the rest of the body and the brain to glucocorticoids. This cell-specific glucocorticoid resistance can be acquired by genetically predisposed individuals failing to cope with (early) life events and causes enhanced vulnerability to disease-specific actions of glucocorticoids. 01997, Elsevier Science Inc. (Trends Endocrinol Metab 1997; 8:26-33).
psychological defense reactions (Munck et al. 1984, De Kloet and Joels 1996). Glucocorticoid secretion and action at the receptor, therefore, need to be tightly controlled in order to facilitate general adaptation. Glucocorticoid secretion is regulated by the hypothalamic-pituitary-adrenal (HPA) axis during stress and circadian variation (Figure 1). The HPA activity is driven by hypothalamic corticotropinreleasing hormone (CRH), vasopressin (VP), and other neuropeptides in various combinations, depending on the nature and the intensity of the stimulus (Herman et al. 1995). The secretagogues are released in a pulsatile fashion from the hypothalamic paraventricular neurons (PVN) into the portal vessels to stimulate pituita~ ACTH release (Plotsky 1991, Antoni 1993, Romero and Sapolsky 1996). Adrenal glucocorticoids rise in level after ACTH stimulation and exert E. RonaldDe IUoet,Emo Vreugdenhil,and MellyS. Oitzlare at the Divisionof Medical negative feedback action on brain and Pharmacology,Leiden/Amsterdam Centerfor pituitary to facilitate recovery of stressDrug Research,LeidenUniversity,2300 RA induced HPA activity (Dallman et al. LeidenTheNetherlands; MarianJoelsis atthe 1992, Dallman 1993). Institutefor NeurobiologyGraduateSchool Glucocorticoid negative-feedback acfor Neuroscience, Universityof Amsterdam, tion is mediated by nuclear glucocorti1098SM Amsterdam,TheNetherlands.
Glucocorticoid hormones (corticosterone in rodents and cortisol in humans) control energy supply through gluconeogenesis and suppress responses to inflammation and infection. They regulate development and aging. They are a critical factor for successful adaptation to stress (Chrousos 1995, McEwen and Sapolsky 1995, Holsboer and Barden 1996). However, if the hormones circulate in aberrant concentrations during chronic stress, they impair adaptation (Sapolsky 1992). Chronic excess of glucocorticoids suppresses the defense reactions to stress and increases the vulnerability to disease. If too little of the hormone is present, the stress response is less effectively restrained, and the individual suffers from the harmful influence of its own excessive physical and
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coid receptors (GRs) localized in the hypothalamic CRH neurons and in the anterior pituitary corticotrophs. Feedback sites containing GRs are also localized in regions outside the hypothalamus. These include the brain stem, where glucocorticoids modulate sensory input to the CRH neurons. In higher brain centers, for example, the hippocampus, glucocorticoids affect cognitive aspects of the stress response, which indirectly have consequences for HPA activity. These effects exerted by cortisol on mood and cognition involve high-affinity mineralocorticoid receptors (MRs), in addition to the lower-affinity GR, (De IUoet 1991). The neural activation of the CRH/VP neurons occurs through norepinephrine, serotonin, and glutamate, whereas y-aminobutyric acid (GABA) is inhibitory (Swanson 1991, Feldman and Weidenfeld 1994). Neuropeptides such as neurotensin, neuropeptide Y, opioids, and substance P, as well as cytokines also modulate the activity of CRH neurons (Chrousos 1995). Glucocot-ticoid feedback involves the genomic control of CRH neurons and corticotrophs and their responsiveness to the aforementioned aminergic and peptidergic mediators of the stress response. The basal level of CRH/VP and ACTH is increased after removal of glucocorticoid feedback by adrenalectomy and already restored after replacement with low amounts of glucocorticoid sufficient to occupy MR. Inhibitory GABA-ergic signals terminating stress-induced CRH/VP release still operate in adrenalectomized animals and are enhanced after glucocorticoid administration. Glucocorticoid feedback resistance implies that glucocorticoid action is inadequate to restrain the hypothalamic CRH/VP drive (Dallman 1993). The inadequate action may be due to reduced bioavailability of free glucocorticoid or impaired receptor function. In the brain, the access to the receptor may be modulated by 1l&hydroxysteroid dehydrogenase (1113-HSD)(Yau and Seckl 1995, Roland et al. 1995, Van Haarst et al. 1996a) or perhaps by P glycoproteins expressed by the multiple drug resistance (mdr) genes in endothelial cells (Bourgeois et al. 1993). Recent research has identified specific defects in GR function as an underlying cause for feedback resistance. These GR defects can be
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feedback resistance
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PATHOLOGY
PHYSIOLOGY
Figure 1. Proposed scheme of the hypothalamic–pituitary-adrenal (HPA) axis under physiological (left) and pathological(right) conditions.For instance,duringdepression,a stateof
hypercorticismdevelops.Glucocorticoidnegativefeedbackand stimulator influencesto the paraventricular neurons(PVN)havereacheda newsetpoint.Thecircadianrhythmis flattened owing to elevatedbasaltroughlevels.Stress-inducedcortisolsecretionis sluggishand long-lasting.The ratio of vasopressin(VP) over corticotropin-releasinghormone (CRH) in the parvocellularPVNis increased.Hypercorticismfacilitatesstimulator signalsfrom brainstem aminergicneurons and attenuatesthe inhibitoryhippocampd influenceon the PVN by changingthe balancein mineralocorticoidreceptor(MR)- and glucocorticoidreceptor(GR)mediated actions.
inherited and/or locally acquired at CRH target neurons. The purpose of this brief review is to examine the characteristics of inherited and acquired impairments in GR function and to evaluate the implication of these receptor deficits in disease susceptibility. We argue here that resistance that is locally acquired in CRH neurons leads to a condition of glucocorticoid dyshomeostasis and increases vulnerability to stress-related disorders.
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Generalized Inherited GlucocorticoidResistance
Individuals diagnosed with signs of generalized inherited glucocorticoid resistance or familial glucocorticoid resistance (FGR) have a mutation or deletion in the GR gene. This receptor abnormality interferes with glucocorticoid feedback signaling in the target organs, including the CRH neurons. As a consethese individuals display quence, hypercorticism. They lack symptoms of Cushing’s syndrome, howeve~ as ACTH and cortisol are set at a higher level to compensate for the generalized GR deficit. If FGR shows clinical symptomatolOgY,it appears to be mainly related to the ACTH-induced hypersecretion of the mineralocorticoid deoxycortisol and the adrenal androgens. Accordingly, the first
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subjects with clinical signs of FGR were diagnosed with hypertension and hypokalemia. They exhibited GRs with reduced binding affinity for glucocorticoids due to a missense mutation predicting a single amino acid substitution in the ligand-binding domain (Hurley et al. 1991). Another Dutch kindred with FGR had a reduced GR number in lymphocytes due to a splice deletion near exon 6 (Karl et al. 1993). The females with this FGR type showed hirsutism, menstrual irregularities, and acne due to the ACTH-induced hypersecretion of androgens (Lamberts et al. 1992a). One unrelated patient was found who suffered from fatigue and resistance to dexamethasone suppression, and a young FGR boy showed sexual precocity. These cases were described in detail in excellent reviews (Stratakis et al. 1994, Malchoff and Malchoff 1995, Bronnegfu-d and Carlstedt-Duke 1995, Bronneg&-d et a]. 1996). Although only few kindreds with severe inherited receptor deficits have been described, recent data suggest a much more frequent occurrence of generalized mutations in the GR gene without apparent clinical symptoms (J.W. Koper and S.W.J. Lamberts personal communication). Also, inherited defects in chaperone proteins (for example, HSP90), receptor-associated transcrip-
tion factors, glucocorticoid response element (GRE), or regulatory regions of GR target genes could similarly result in mild deficits in receptor function. It is conceivable, however, that such receptor variants produce cortisol dysfunction that may become harmful only during conditions of chronic stress. Preliminary observations indeed suggest signs of feedback resistance in healthy subjects at genetic risk for depression (Holsboer et al. 1995). Of course, proof of this thesis must await the actual manifestation of depression in these individuals. Although severe inherited deficits in GRs resulting in asymptomatic hypercorticism seem a rare disorder in humans, some species such as guinea pigs, prairie voles, and new-world monkeys have receptor deficits by nature. The guinea pig shows generalized mutations in the GR gene, causing reduced affinity of GR for cortisol. The ACTH molecule is changed to a much more potent “super agonist” (Keightly and Fuller 1994). There is normal circadian variation in HPA activity but ACTH and cortisol are circulating at a much higher level. Apparently, the strongly elevatedset point in HPAactivity in these animals has proved to be an adequate adaptation,given their evolutionary success (Funder 1994). Even the complete lack of GR is not incompatible with life, as was recently found in transgenic mice homozygous for targeted disruption of the GR gene (Cole et al. 1995). The mice were generated by introduction of a null mutation in the mouse GR gene and subsequent targeting of embryonic stem cells. Although most GR-deficient mice die shortly after birth owing to respiratory failure, a few (5%-IO% of the newborns) survive. These survivors show a complete lack of adrenal medulla and, thus, of circulating epinephrine. They have greatly enlarged adrenal cortices and very high ACTH and corticosterone levels. Neither the homozygous nor the heterozygous animals show signs of adrenal insufficiency or Cushing’s syndrome, respectively.A closer look at the behavioral studies revealed a memory deficit (M.S. Oitzl personal communication), and an electrophysiological survey (M. Joels personal communication) revealed disturbances in ion regulation, which can be ascribed to lack of brain GRs. In conclusion, FGR in humans is a rare disorder characterized by a general-
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Figure2. The molecular basis of glucocorticoid resistance. Glucocorticoids (red triangles)pass the cell membrane and bind to the glucocorticoid receptor (GR) at the carboxy-terminal steroid-binding site (indicated in yellow). Upon binding of glucocorticoids, the receptor is translocated to the nucleus. (A) Transactivation of steroid receptor: DNA-binding site of the receptor (indicated in orange) recognizes specific DNA sequences, the glucocorticoid response elements (GREs). This binding will direct the transcription of genes containing GREs. (B) Transrepression: activated GRs may also repress the activity of other transcription factors by direct protein-protein interaction. (C) Transcription factors (TF) (indicated in dark blue): TFs such as activating-protein I (AP-1) and nuclear factor-KB (NFKB) are normally activated by inflammatory processes or stress and, as the GR, bind to specific DNA sequences (TF sites, indicated in gray), thus directing the transcription of specific target genes. Glucocorticoid resistance develops when the action of TFs is insufficiently restrained by GRs. Two alternative splice variants of the GR are generally expressed as the GRci and the GR~ (see light yellow box). The GR~ does not bind glucocorticoids, but it may interfere with transcription activation of the GRw Several naturally occurring point mutations leading to amino acid substitutions and one deletion have been characterized in the GRa(seelight yellow box). Especially, mutations in the steroid-binding domain (indicated in darkyellow) will lead to aberrant steroid-binding capacities and, thus, to malfunctioning of process of transactivation (situation A). In addition, as part of this GR domain and the, domains are also involved in the binding of other TFs, transrepression (situation B) is also severely affected. This malfunctioning of the GR in both transactivation and transrepression may facilitate the development of glucocorticoid resistance.
ized GR deficit that does not result in glucocorticoid-dependent pathological processes in view of adaptation in the set point of HPA activity. However, GR vari-
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ants may exist that only under conditions of high demand promote dysregulation in glucocorticoid action and increase risk of disease.
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Acquired Glucocorticoid Resistance
Tissue-specific glucocorticoid resistance generally does not produce a compensatory rise in circulating cortisol level. Such local resistance may be acquired during inflammato~ processes, which then explains the need for treatment with potent synthetic glucocorticoids. For instance, two categories of glucocorticoid-resistant asthma patients were distinguished (Barnes and Adcock 1993, Kam et al. 1993). The rare type II form of resistance is irreversible. It is characterized by a reduced number of GRs and normal binding affinity, suggesting some resemblance to FGR. Yet, type I resistance is characterized by reduced affinity and increased binding capacity of GR in T-lymphocytes. In culture, this GR defect is reversible, but it is maintained upon coincubation with interleukin (IL)-2 and IL-4. The action of these cytokines, therefore, may be causal to in-
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adequate GR function. Likewise, GR deficits may also be associated with susceptibility to other inflammatory or immune disorders (for example, rheumatoid arthritis or multiple sclerosis) due to locally evoked disturbances by inflammatory mediators (Kam et al. 1993). How can local steroid resistance be acquired? One cause may be tissue-specific receptor mutation, but evidence for this was so far only found in tumors of a patient suffering frOITINelson syndrome (Stratakiset al. 1994).Another cause may be alternativesplicing of the GR gene. A hGR~ variant was found widely distributed in addition to the common hGR (hGRa) (Bamberger et al. 1995and 1996). Glucocorticoids do not bind to GR@. Cotransfection of COS-7 monkey kidney tumor cells with both isofonns revealed that the GR~ form is transcriptionallyinactive. GR~, however, blocks the effect of GR-mediated transactivationin a concentration-dependent manner, although it does not seem to interfere with transrepression (Bamberger et al. 1996). In newworld monkeys, overexpression of the GRp variant is observed, which could explain their glucocorticoid feedback resistance. Cidlowski et al. (1996) recently observed that the GR~ variantwas preferentiallyinduced over GRa after exposure to cytokines. A second category of factors inducing steroid resistance is indicated by recent data on crosstalk between nuclear receptors and membrane signaling cascades. One possibility is the change in receptor properties through enzymatic modifications, for example, phosphorylation in response to peptides and transmitters (Zhang et al. 1994). Another possibility (Figure 2) is the interaction of GR with nonliganded transcription factors such as activatingprotein I (API), cAMP response element-binding protein (CREB), or nuclear factor KB(NFKB)(Pfahl 1993).These proteins are activated by membrane-signalingpathwaysin response to inflammatory, immune, and stress mediators (for example, cytokines, excitatory amino acids, and biogenic amines). GRs repressthe generally positive effects of AP1, CREB, and NFKB on gene transcription either directly via composite GREs or indirectly by protein–protein interaction. Inadequate repression by GR is characteristic for steroid resistance during inflammatory and immune disorders. Glucocorticoid resistance may also be related to inTEM vol. 8, No. 1, 1997
creased GR polymorphism in the T2 do-
few days in elevated corticosteroid levels
main (Barnes and Adcock 1993). Mutations in this receptor domain impair interaction with transcription factors,
during the circadian rise and in response to stress, CRH mRNA, ACTH, and basal trough corticosterone are not changed, but the adrenocortical sensitivity to ACTH is increased (Van Haarst et al. 1996b). Third, impairment of adrenocortical function is a possible way by which the balance of excitatory and inhibitory signals in the PVN is changed. For instance, if rats are treated with the steroid-synthesis inhibitor cyanoketone, their corticosterone response to stress is facilitated (Akana and Dallman 1992, Dallman et al. 1992, Dallman 1993). Alternatively, reset of feedback sensitivity occurs when the input from multiple sensory signaling pathways converging on CRH neurons becomes disproportionate (Figure 1). This occurs with physical stressors, for example, evoked by infection, trauma, inflammation, respiratory distress, or hemorrhage. These stressors activate brain stem aminergic neurons, which stimulate CRH and VP synthesis directly through al adrenergic receptors (Plotsky 1991). Disproportionate input to CRH neurons can also be due to cognitive stimuli, which may become particularly potent chronic stressors under conditions of anxiety, uncertainty, lack of control, or poor predictability of upcoming events, either real or imagined. The elevated glucocorticoid levels caused by such chronic physical and psychological stressors produce tolerance for elevated glucocorticoids through downregulation of GRs in the CRH/VP neurons (De Kloet 1991). The lower GR number would allow a reduced magnitude of the glucocorticoid signal and, as consequence, a further dysregulation of the HPA axis. The anatomicalsubstratefor processing of cognitive stimuliis the limbic-forebrain circuit~ including the hippocampus, a brain structure involved in regulation of mood, learning, and memory processes (Chan-PalayandKohler 1989).Input from locus coeruleus noradrenergic, raphe serotonergic, and mesocortical dopaminergic neurons modulates the processing and appraisalof environmentalinformation in these higher brain circuits. Importantly a rise in glucocorticoids, in turn, promotes stress-inducedactivationof these serotonergic, dopaminergic, and noradrenergic neurons in the brain stem and increases the sensitivityof limbic-forebrain areas to the aminergic inputs (McEwen 1987).
whereas the binding to DNA or steroids is not hampered. In conclusion, glucocorticoid resistance is acquired by local changes in the receptor state, the local generation of different receptor variants, or altered crosstalk of GR with other signaling pathways. Possibly, inherited defects in the GR may facilitate the acquisition of resistance.
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GlucocorticoidFeedback Resistancein Neural Stress Response Circuitry
Glucocorticoid resistance acquired in CRH neurons becomes manifest if feedback control of stress-induced activation of CRH neurons fails. The principal feature of glucocorticoid resistance in CRH neurons is the same as seen with, for example, asthma or arthritis: The balance between GR function on the one hand and the drive of converging signal transduction pathways and transcription factors on the other hand is disturbed (Figure 1). However, the site of resistance, that is, the very neurons where feedback control is regulated, is crucial. The resistance to glucocorticoid feedback in CRH neurons causes increased HPA activity and produces hypercorticism. As an unfortunate consequence, the rest of the body and the brain, including the neural stress response circuitry, suffers from glucocorticoid overexposure. One way in which the balance just described can be disturbed is when a local GR deficit exists. This can be an inherited property, as is demonstrated in the recently engineered transgenic mouse line with brain-selective reduced expression of the GR. Such mice display hypercorticism, cognitive impairment, and metabolic disturbances that in many aspects resemble the symptoms of Cushing’s syndrome (Barden et al. 1995). Second, it can also be.acquired, as is shown by a pharmacological approach using chronic daily administration of 200 mg/day of the antiglucocorticoid RU 486 (Lamberts et al. 1992b). If RU 486 is infused continuously (100 rig/day) into the brain ventricles of rats, the chronic blockade of brain GR results within a
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PATHOLOGY Figure 3. Mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are colocalized in hippocampal neurons. Their relative activation depends on the circulating corticosteroid level. During physiological conditions, MRs are considerably occupied even with low corticosteroid levels, as occurs during the circadian trough; GRs are onfy partly occupied (upper panel). When corticosteroid levels rise, for example, after acute stress, most of the GRs will be activated in addition to the MRs (middle panel). Cellular properties of hippocampal neurons carrying MRs and GRs are modulated by steroid receptor activation. Predominant MR activation results in stable amino acid–mediated transmission, small Ca influxes, and small aminergic responses. In general, this is a favorable condition for neuronal stability. With additional GR activation, amino acid responses are reduced, and Ca influx is large. At a short scale, this may serve to reverse stress-induced hippocampal excitation. The MR- and GRmediated cellular effects have consequences for functions in which the hippocampus plays an important role, such as cognition and (transsynaptically) the regulation of hypothalamic– pituitary-adrenal (HPA) activity. Chronic hypercorticism associated with glucocorticoid feedback resistance leads to chronic activation of MRs and GRs (lower panel). GR-mediated events such as reduction of inhibitory amino acid responses and increased Ca influx, which at a short time scale are beneficial, now increase vulnerability to neurodegenerative processes. At least in part because of these detrimental effects, cognitive impairment occurs, and the process of steroid resistance is (transsynaptically) exacerbated. These include the direct aminergic input to the CRH/VP neurons, as well as the
indirect route to these CRH neurons via the hippocampus. By this reinforcing
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mechanism, the feedback resistance at the
level of the CRH neurons is increasin~y aggravated. The ensuing hypercorticism and arninergic sensitization potentially
enhances the organism’s vulnerability to brain disorders such as addiction (Piazza et al. 1991) and depression (Chrousos 1995, Holsboer and Barden 1996). A single traumatic life event is often sufficient to trigger this vicious circle in glucocorticoid-amine interactions and to precipitate stress-related disorders. The effect of psychosocial distresscan be demonstrated in rats after a decisive defeat (Bohus et al. 1987) or even after exposure to one session of inescapable footshocks (Van Dijken et al. 1993).After these single traumatic events, feedback resistance slowly evolves over a period of several weeks. The most persistent effects are, however,observed after an early life experience. Three-day-old rats deprived of their mother for 24 h display as adults, hypercorticism and downregulation of GR.s in the hypothalamic PVN. The deprived animals also display increased nigrostriatal- and tubero-infundibular dopamine reactivity (Rots et al. 1996a). There are, however, sex and strain differences in the effect of early life experience, and the time point and the duration of the maternal separation procedure also modulates development of the adult phenotype. Interestingly, maternal separation restricted to 15 min per day causes the opposite effect. Such socalled handled animals have a reduced emotional and adrenocortical reactivity (Levine 1994, Meaney et al. 1988). The outcome of mother–pup interaction is further superimposed on genotype. For instance, rat lines genetically selected for extreme differences in susceptibility to apomorphine showed developmental changes in HPA reactivity, which preceded the divergence in dopamine phenotype (Rots et al. 1996b). In conclusion, the set point of HPA activity is programmed by genotype but can be changed to another level by early life events. This reset of HPA activity evolves slowly and may lead to a vicious circle of enhanced input to CRH neurons, feedback resistance, and hypercorticism. These inputs originate from brain stem and limbic circuits.
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Role of Hippocampus in Feedback Resistance
As discussed earlier here, the functional outcome of limbic (hippocampal) circuitry is important for the activity of CRH neurons. What adds to the com-
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plexity of this influence of higher brain structures on stress physiology is that the hippocampus itself forms a prime target for corticosteroid hormones. Elevated corticosteroid levels, which are the basis as well as a consequence of feedback resistance in the hypothalamus, will therefore indirectly, via the hippocampus, determine the nature of the influence exerted by higher brain structures. How do they accomplish this? Hippocampal cells express MRs and GRs (De Kloet 1991). Cortisol and corticosterone bind with a 10-fold higher affinity to MRs than to GRs. Because of this, high-affinity MRs are already predominantly occupied by low basal corticosteroid levels. GRs become activated additionally to MRs when steroid levels rise, for example, after stress and toward the circadian peak. It was shown that MR and GR activation affect local signal transduction differently (Joels and De Kloet 1992 and 1994). Therefore, the relative MRIGR occupation in a hippocampal cell determines how cellular events and the hippocampal networks in which the cells participate are affected (Figure 3). These hippocampal networks in turn play a role in mood and cognition (Oitzl and DeKloet 1992, McEwen and Sapolsky 1995) and also in fear and anxiety (Korte et al. 1995). They indirectly regulate CRH neurons via a poorly understood transsynaptic pathway involving an inhibitory GABA-ergic input to the PVN (Swanson 1991). MR expression is high in hippocampus and other limbic structures but virtually absent from CRH neurons. Studies in rats have demonstrated that low levels of corticosterone acting through these extrahypothalamic MRs are already sufficient to suppress HPA activity. In adrenalectomized rats,basal-troughACTHlevelswere obtained, if corticosterone levels are kept constant at about 100 nM (= 0.8 nM free steroid) via replacementwith slow-release corticosterone pellets. Circadian rises in HPAactivitywere blocked when sufficient corticosterone was provided to activate GRs, but the occupation of MRs was indispensablefor this effect (Bradbury et al. 1994). A variety of experimental conditions have also demonstrated the significance of hippocampal MR in control of the HPA tone. First, pharmacological blockade with MR antagonists increased basal and stress-induced HPA activity (Ratka TEM vol. 8, No. 1, 1997
Figure4. 3H-Corticosterone binding in the dorsal hippocampus of interleukin (IL)-1 treated rats. Seven-day adrenalectomized rats were injected intracerebroventricular (icv) with vehicle (left) or 100 ng IL-1 (right). After 2 h the animals were given subcutaneous injections of tracer 3H-corticosterone. Three hours after the injection, IL-1 or vehicle (that is, 1 h after injection of the radiolabeled tracer) animals were killed, the brain was cut, and the sections exposed to autoradiographic film. The experiment demonstrates that tracer amounts of 3H-corticosterone are retained selectively by the mineralocorticoid receptor (MR). IL-1 impairs steroid retention by reducing the affinity of MR. The figure is modified &orn Schobit~ et al. (1994). et al. 1989, Bradbuv et al. 1994). Second, in females, the cyclic increase of HPA activity at the evening of proestrus occurs when the high estrogen and progesterone levels impair MR function (Carey et al. 1995). Third, rat strains with high hippocampal MR expression (for example, Lewis rats) show lower HPA activity (Oitzl et al. 1995). Fourth, aged individuals have generally reduced MR expression and increased HPA activity (Van Eekelen et al. 1995). Finally, tricyclic antidepressants increase hippocampal MRs and decrease HPA activity (Yau et al. 1995, Holsboer and Barden 1996). The previous examples concern physiological events, but in the pathophysiological realm, MR function also affects HPA activity. IL-1 administration causing hypercorticism and fever reduces affinity of corticosterone to MRs in hippocampus (Figure 4). The impaired MR function is paralleled by a pronounced increase in set point of HPA activity (Schobitz et al. 1994). Cytokine-induced resistance was also noted in GRs in lymphocytes during septic shock (Molijn et al. 1995) and, as mentioned previously, in T-lymphocytes of asthma patients. It is not known whether this effect of cytokines involves a direct influence on the receptor or is achieved indirectly via the elevated temperature. The output of the hippocampus activates an inhibito~ GABA-ergic input to the CRH neurons, which is maintained via MRs. Hippocampal GR activation produces opposite effects (Joels and De Kloet 1994) and counteracts the inhibitory control over CRH neurons. Moreover, chronic high glucocorticoid levels
impair cognitive processes and behavioral adaptation. The authors propose that the effects of chronic psychological stress in the development of glucocorticoid feedback resistance are reinforced, at a later stage, by elevated corticosteroid levels acting via MRs and GRs in the hippocampus. In summary, these observations show that MR-controlled input from extrahypothalamic structures is critical for the tone of the HPA activity. It remains to be shown if dysregulation of the HPAaxis is a consequence of impaired action at higher brain centers or if it primarily develops at the level of the PVN. Relevant to the situation of glucocorticoid resistance is that excess of corticosteroids impairs cognitive performance and signaling in the hippocampus, which indirectly also affects CRH synthesis (Wolkowitz 1994, McEwen and Sapolsky 1995, De Kloet and Joels 1996). .
Conclusion
A fundamental question in stress research is how or at what time glucocorticoid hormones stop facilitating adaptation and start increasing vulnerability to damage. The present review has demonstrated that acquired feedback resistance is one criterion to discriminate “good” from “bad” steroid action. Such resistance develops when excitatory influences override glucocorticoid feedback and reset the tone of the HPA axis. This condition is representative for a range of stress-related disorders, including depression and anorexia. Alternatively supersensitivity to glucocorticoid feedback also exists. This
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condition of enhanced feedback results in lower tone of HPA activity and, thus, hypocorticism and reduced 24-h cortisol production. Reduced glucocorticoid exposure due to enhanced negative feedback efficacy was recently also recognized as a pathological condition. It is characteristic for posttraumatic stress disorder (Yehuda 1996). Chronic fatigue syndrome (Chrousos 1995) and fibromyalgia (Griep et al. 1993) also show features of secondary adrenocortical deficiency of central origin. Increasing evidence suggests that the primary defect in these disorders of the stress-response system is related to the function of MRs and GRs in the brain. Future research may elucidate whether polymorphisms in MRs and GRs predispose for stress-related disorders, particularly during chronic psychosocial stress. Knowledge of the properties of hippocampal MRs and its splice variants is essential, as it is this receptor type that regulates the tone of the HPA activity and the neuronal processes in higher brain regions underlying perception and cognitive performance. It will be a challenge to unravel how these higher brain centers communicate with the endocrine system, and what defects in MRs and GRs disturb an effective dialogue with corticosteroid hormones. This would allow the identification of dysregulated genes as potential targets for treatment of stress-related disorders.
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Bamberger CB, Schulte HM, Chrousos GP: 1996. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev 17:245–261. Barden N, Reul JMHM, Holsboer F: 1995. Do anti-depressantsstabilize mood on the hypothalamic-pituitary-adrenocortical system? TrendsNeurosci 18:6-14. Barnes PJ, Adcock I: 1993. Anti-inflammatory actions of steroids: molecular mechanisms. TrendsPharmacol Sci 14:436-441.
The support by the Netherlands Organization for Scientific Research (NWO) is gratefully acknowledged. We thank Ms. Ellen M. Heidema for editorial assistance.
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Bronneg5rdM, Carlstedt-DukeJ: 1995. The genetic basis of glucocorticoid resistance. TrendsEndocrinol Metab 6:160-164.
Holsboer F Lauer CJ, SchreiberW, et af.: 1995. Alteredhypothalamic-pituitary-admmd regulation in healthysubjectsat high familiafriskfor depression.Neumendocrinology62:346347.
Griep ED, Boersma JW, De Kloet ER: 1993. Bourgeois S, Gmul D, Newby R, et al.: 1993. Altered reactivity of the hypothalamic-pituExpressionof an mdrgene is associatedwith a itary-adrenalactivityin the fibromyafgia synnew form of resistanceto dexamethasone-indrome. J Rheumatol 20:469-474. duced apoptosis.Mol Endocrinol 7:840-851. Herman JP,Adams D, PrewittC: 1995. RegulaBradbury M, Akana SE Dallman MF: 1994. tory changes in neuroendocrine stress inteRoles of TWe 1 and Type 2 corticosteroid grative circuitry produced by a variety of receptorsin the regulationof basaf activityin stress paradigms. Neuroendocrinology 61: the hypothalamic-pituitary-adrenalaxis dur180-190. ing the diurnal trough and peak: evidencefor Holsboer F, Barden N: 1996. Antidepressants a non-additive effect of combined receptor and hypothalamic-pituitary-adrenocortical occupation. Endocrinology 134:1286-1296. regulation. Endocr Rev 17:187–205.
Bronneg?wdM, Stiema P,Marcus C: 1996. Glucocorticoid-resistant syndromes: molecukubasis and clinical presentations.J Neuroendocrinol 8:405-415. CareyMP,DeterdCH, De Koning J, et al.: 1995. The influence of ovariansteroidson hypothalamic-pituitary-adrenal regulation. J Endocrinol 144:311–321.
Chrousos GP: 1995. The hypothalamic– pituitary-adrenalaxis and immune-mediated inflammation. N Engf J Med 332:1351–1359. Cidlowski JA, Oaldey RH, Webster JC, et al.: 1996. Characterizationand regulation of the beta isofonn of the human glucocorticoid receptor [abst P2-847]. In Proceedings of the 70th Annuaf Meeting of the Endocrine Society SanFrancisco, CA, p 616. Cole TJ, Blendy JA, Monaghan AP,et al.: 1995. Targeteddisruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev 9:1608–1621. DallmanMF: 1993.Stressupdate:adaptationof the hypothalamic-pitui~-adren~ axis to chronic stress. Trends Endocrinol Metab 4:62-69.
BarnbergerCB, BarnbergerAM, De CastroM, et Dallman MF, Akana SF, Scribner KA, et af.: 1992. Stress,feedback and facilitation in the al.: 1995.Glucocorticoidreceptor13,a potentiaJ hypothafambpituitary-adrenal axis. J Neuendogenous inhibitor of gfucocorticoid action roendocnnol 4:517–526. in humans.J Clin Invest95:2435–2441.
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De Kloet ER, Jc& M: 1996. Corticosteroidhormones in neuroprotection and brain damage. Curr Opin Endocrinol 3:184-192.
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Chan-PalayV,KohferC: 1989.TheHippcarnpus: New Vistas.Neurologyand Neurobiology vol. 52. New York,Alan Liss.
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Hurley DM, Accifi D, StratakisCA, et al.: 1991. Point mutation causing a singfe amino acid substitutionin thehormonebindingdomain of the glucocorticoid mxptor in famifiaf gfucocorticoid resistance.J ClinInvest87:680-686. Joels M, De Kloet ER: 1992. Control of neuronal excitability by corticosteroid hormones. Trends Neurosci 15:25–30. Joels M, De Kloet ER: 1994. Minerafocorticoid and glucocorticoid receptorsin the brain: implications for ion permeability and transmitter systems. Prog Neurobiol 43:1–36. Kam JC, Szefler SJ, Surs W, et af.: 1993. Combination of IL-2 and IL-4 reduces glucocorticoid receptor binding affinity and T cell response to glucocorticoid therapy. J Clin Invest 93:33–39. Karl M, Lamberts SWJ, Detera-Wadleigh SD: 1993. Familiaf glucocorticoid resistance caused by a splice deletion in the human glucocorticoid receptor gene. J Clin Endocrinol Metab 76:683489. KeigthlyMC, FullerPJ: 1994.Unique sequences in the guinea pig glucocorticoid receptor induce constitutive transactivation and decrease steroid sensitivity Mol Endocrinol 8:431439. Korte SM, De Boer SFjDe Kloet ER, et al.: 1995. Anxiolytic-likeeffectsof selectiveminerafocorticoid and glucccorticoid antagonistson fezm enhancedbehaviorin elevatedplus maze. Psychoneuroendocrirsology20:385--394.
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Lamberts SWJ, Koper JW, Biemond P, et aL: 1992a. Cortisol receptor resistance:the wu-iabilityof chnical presentationand responseto treatment.Clin Endocrinol Metab 74:313–321. Lamberts SWJ, Koper JW, De Jong FH: 1992b. Long-termtreatmentwith RU 486 and glucocorticoid receptor resistance:theoreticaland therapeuticalimplications. TrendEndocrinol Metab 3:199-205. LevineS: 1994.The ontogenyof thehypothalamic-pituitruy-achenal axis:theinfluenceof maternaf factors.Ann NY Acad Sci 746:275–293. Malchoff CD, Malchoff DM: 1995. Glucocorticoid resistance in man. Trends Endocrinol Metab 6:89–94. McEwen BS: 1987. Glucocorticoid-biogenic amine interaction in relation to mood and behavior.Biochem Pharmacol 36:1755-1763. McEwen BS, Sapols& RM: 1995. Stress and cognitive function. Curr Opin Neurobiol 5:205-217. Meaney MJ, Aitken DH, Van Berkel C, et aL: 1988. Effect of neonatal handling on agerelated impaimnentsassociated with hippocampus. Science 239:766-768. Molijn GM, Spek JJ, Van Uffelen CJC, et al.: 1995. Differential adaptation of glucocorticoid sensitivityof peripheralblood mononuclear leukocytes in patients with sepsis or septic shock. J Clin Endocrinol Metab 80: 1799-1803. Munck A, McGuire PM, Holbrook NJ: 1984. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 5:2544. OitzlMS, De Kloet ER: 1992.Selectivecorticosteroid antagonists modulate specific aspects of spatial orientation learning. Behav Neurosci 106:62–71. Oitzl MS, Van Haant AD, Sutanto W, et aL: 1995. Corticosterone, brain mineralocorticoid receptors (MRs) and the activity of the hypothalamic-pituitary-adrenal axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsiveHPAaxis. Psychoneuroendocrinology 20:655-677. Pfahl M: 1993. Nuclear/receptor AP-1 interaction. Endocr Rev 14:651–658. Piazza PV, Maccari S, Deminiere JM, et al.: 1991. Corticosterone levels determine individual vulnerabilityto amphetamine self-administration. Proc Nad Acad Sci USA 88: 2088-2092. Plotsky P: 1991. Pathways to the secretion of adrenocorticotropin: a view from the portal. J Neuroendocrinol 3:1–9. Ratka A, Sutanto W, Bloemers M, et aL: 1989. On the role of brain mineralocorticoid (type 1) and glucocorticoid (type 2) receptors in neuroendocrine regulation. Neuroendocrinology 50:117–123. Roland BL, KI_OZOWSki ZL, Funder JIM 1995. Glucocorticoid receptor, mineralocorticoid
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receptor, 11~-hydroxysteroid dehydrogenase-1 and -2 in rat brain and kidney: in situ studies. Mol Cell Endocrinol 28:R1–R7.
long-lasting changes in the brain–pituitaryadrenal axis of adult male rats. Neuroendocnnology 58:5764.
Romero LM, Sapolsky RM: 1996. Patterns of ACTH secretagogue secretion in response to psychological stimuli. J Neuroendocrinol 8:243-258.
Van EekelenJAM,Oitzl MS, De Kloet ER: 1995. Adrenocortical hyporesponsiveness and glucocorticoid feedback resistancein old Brown Norway rats. J Gerontol 50A:B83-B89.
Rots ~, De Jong J, Workel JO: 1996a. Neonatally deprived rats have as adults elevated basal pituitary-adrenalactivityand enhanced susceptibilityto apomorphine. J Neuroendocrinol 8:501–506.
VanHaarstAD, WelbergLAM, SutantoW, et al.: 1996a. 11~-hydroxysteroiddehydrogenasein the hippocampus: implications for corticosterone binding and nuclear retention.J Neuroendocnnol 8:595400.
Rots ~, Cook AR, Oitzl MS, et aL: 1996b, Divergentprolactin and pituitary-adrenalactivity in rats selectively bred for different dopamine responsiveness. Endocrinology 137:1678-1686.
Van HaarstAD, Oitzl MS, Workel JO, De Kloet ER: 1996b. Chronic brain glucocorticoid receptor blockade enhances the rise in circadian and stress-inducedpituitary-adrenalactivity.Endocrinology 137:4935-4943.
SapolskyRM: 1992.Stress,the AgingBrain and the Mechanism of Neuron Death. Cambridge, MA, MIT Press.
Wolkowitz OM: 1994. Prospective controlled studies of the behavioral and biological effects of exogenous corticosteroids. Psychoneuroendocrinology 19:233–255.
Schobitz B, Sutanto W, Carey MP, et aL: 1994. Endotoxin and interleukin-1decrease the affinity of hippocampal mineralocorticoid (type 1) receptor parallel to activation of the hypothalamic-pituitary-adrenal axis. Neuroendocrinology 60:124133. StratakisCA, Karl M, Schulte H, et a].: 1994. Glucocorticoid resistance in humans: elucidation of the molecular mechanisms and implications for pathophysiology.Ann Ny Acad Sci 746:362-377. Swanson LW: 1991. Biochemical switching in hypothalamic circuits mediating responses to stress.Prog Brain Res 87:181–200. Van Dijken HH, De Goeij DCE, Sutanto W, et al,: 1993. Short inescapable stress produces
Yau JLW, Secld JR: 1995. Corticosteroids and the bmin. Curr Opin Endocrinol 2:239–247. Yau JLW,Olsson T, Morris RGM, et aL: 1995. Glucocorticoids, hippocampal corticosteroid receptor gene expressionand anti-depressant treatment.Relationship with spatial learning in young and aged rats.Neurosci 66:571-581. Yehuda R: 1996. Increased pituitary activation following metyrapone administration in post-traumatic stress disorder. Psychoneuroendocrinology 21:1–16. Zhang x Bai W, AIlgood VE, et al.: 1994. Multiple signaling pathways activatethe chicken progesterone receptor. Mol Endocrinol 8:577-585. TEM
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Glucocorticoid feedback resistance can be inherited or locally acquired. The implications of these two forms of resistance for disease are strikingly different. The inherited form is characten”zed by enhanced adrenocortical function and hypercorticisrn to compensate for a generalized deficit in the glucocorticoid receptor gene, but these individuals lack symptoms of Cushing’s syndrome. By contrast, resistance acquired at the level of the hypothalamic corticotropin-releasing hormone (CRH) neurons is linked to hypercorticism, which is not compensatory but overexposes the rest of the body and the brain to glucocorticoids. This cell-specific glucocorticoid resistance can be acquired by genetically predisposed individuals failing to cope with (early) life events and causes enhanced vulnerability to disease-specific actions of glucocorticoids. 01997, Elsevier Science Inc. (Trends Endocrinol Metab 1997; 8:26-33).
psychological defense reactions (Munck et al. 1984, De Kloet and Joels 1996). Glucocorticoid secretion and action at the receptor, therefore, need to be tightly controlled in order to facilitate general adaptation. Glucocorticoid secretion is regulated by the hypothalamic-pituitary-adrenal (HPA) axis during stress and circadian variation (Figure 1). The HPA activity is driven by hypothalamic corticotropinreleasing hormone (CRH), vasopressin (VP), and other neuropeptides in various combinations, depending on the nature and the intensity of the stimulus (Herman et al. 1995). The secretagogues are released in a pulsatile fashion from the hypothalamic paraventricular neurons (PVN) into the portal vessels to stimulate pituita~ ACTH release (Plotsky 1991, Antoni 1993, Romero and Sapolsky 1996). Adrenal glucocorticoids rise in level after ACTH stimulation and exert E. RonaldDe IUoet,Emo Vreugdenhil,and MellyS. Oitzlare at the Divisionof Medical negative feedback action on brain and Pharmacology,Leiden/Amsterdam Centerfor pituitary to facilitate recovery of stressDrug Research,LeidenUniversity,2300 RA induced HPA activity (Dallman et al. LeidenTheNetherlands; MarianJoelsis atthe 1992, Dallman 1993). Institutefor NeurobiologyGraduateSchool Glucocorticoid negative-feedback acfor Neuroscience, Universityof Amsterdam, tion is mediated by nuclear glucocorti1098SM Amsterdam,TheNetherlands.
Glucocorticoid hormones (corticosterone in rodents and cortisol in humans) control energy supply through gluconeogenesis and suppress responses to inflammation and infection. They regulate development and aging. They are a critical factor for successful adaptation to stress (Chrousos 1995, McEwen and Sapolsky 1995, Holsboer and Barden 1996). However, if the hormones circulate in aberrant concentrations during chronic stress, they impair adaptation (Sapolsky 1992). Chronic excess of glucocorticoids suppresses the defense reactions to stress and increases the vulnerability to disease. If too little of the hormone is present, the stress response is less effectively restrained, and the individual suffers from the harmful influence of its own excessive physical and
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coid receptors (GRs) localized in the hypothalamic CRH neurons and in the anterior pituitary corticotrophs. Feedback sites containing GRs are also localized in regions outside the hypothalamus. These include the brain stem, where glucocorticoids modulate sensory input to the CRH neurons. In higher brain centers, for example, the hippocampus, glucocorticoids affect cognitive aspects of the stress response, which indirectly have consequences for HPA activity. These effects exerted by cortisol on mood and cognition involve high-affinity mineralocorticoid receptors (MRs), in addition to the lower-affinity GR, (De IUoet 1991). The neural activation of the CRH/VP neurons occurs through norepinephrine, serotonin, and glutamate, whereas y-aminobutyric acid (GABA) is inhibitory (Swanson 1991, Feldman and Weidenfeld 1994). Neuropeptides such as neurotensin, neuropeptide Y, opioids, and substance P, as well as cytokines also modulate the activity of CRH neurons (Chrousos 1995). Glucocot-ticoid feedback involves the genomic control of CRH neurons and corticotrophs and their responsiveness to the aforementioned aminergic and peptidergic mediators of the stress response. The basal level of CRH/VP and ACTH is increased after removal of glucocorticoid feedback by adrenalectomy and already restored after replacement with low amounts of glucocorticoid sufficient to occupy MR. Inhibitory GABA-ergic signals terminating stress-induced CRH/VP release still operate in adrenalectomized animals and are enhanced after glucocorticoid administration. Glucocorticoid feedback resistance implies that glucocorticoid action is inadequate to restrain the hypothalamic CRH/VP drive (Dallman 1993). The inadequate action may be due to reduced bioavailability of free glucocorticoid or impaired receptor function. In the brain, the access to the receptor may be modulated by 1l&hydroxysteroid dehydrogenase (1113-HSD)(Yau and Seckl 1995, Roland et al. 1995, Van Haarst et al. 1996a) or perhaps by P glycoproteins expressed by the multiple drug resistance (mdr) genes in endothelial cells (Bourgeois et al. 1993). Recent research has identified specific defects in GR function as an underlying cause for feedback resistance. These GR defects can be
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feedback resistance
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PATHOLOGY
PHYSIOLOGY
Figure 1. Proposed scheme of the hypothalamic–pituitary-adrenal (HPA) axis under physiological (left) and pathological(right) conditions.For instance,duringdepression,a stateof
hypercorticismdevelops.Glucocorticoidnegativefeedbackand stimulator influencesto the paraventricular neurons(PVN)havereacheda newsetpoint.Thecircadianrhythmis flattened owing to elevatedbasaltroughlevels.Stress-inducedcortisolsecretionis sluggishand long-lasting.The ratio of vasopressin(VP) over corticotropin-releasinghormone (CRH) in the parvocellularPVNis increased.Hypercorticismfacilitatesstimulator signalsfrom brainstem aminergicneurons and attenuatesthe inhibitoryhippocampd influenceon the PVN by changingthe balancein mineralocorticoidreceptor(MR)- and glucocorticoidreceptor(GR)mediated actions.
inherited and/or locally acquired at CRH target neurons. The purpose of this brief review is to examine the characteristics of inherited and acquired impairments in GR function and to evaluate the implication of these receptor deficits in disease susceptibility. We argue here that resistance that is locally acquired in CRH neurons leads to a condition of glucocorticoid dyshomeostasis and increases vulnerability to stress-related disorders.
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Generalized Inherited GlucocorticoidResistance
Individuals diagnosed with signs of generalized inherited glucocorticoid resistance or familial glucocorticoid resistance (FGR) have a mutation or deletion in the GR gene. This receptor abnormality interferes with glucocorticoid feedback signaling in the target organs, including the CRH neurons. As a consethese individuals display quence, hypercorticism. They lack symptoms of Cushing’s syndrome, howeve~ as ACTH and cortisol are set at a higher level to compensate for the generalized GR deficit. If FGR shows clinical symptomatolOgY,it appears to be mainly related to the ACTH-induced hypersecretion of the mineralocorticoid deoxycortisol and the adrenal androgens. Accordingly, the first
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subjects with clinical signs of FGR were diagnosed with hypertension and hypokalemia. They exhibited GRs with reduced binding affinity for glucocorticoids due to a missense mutation predicting a single amino acid substitution in the ligand-binding domain (Hurley et al. 1991). Another Dutch kindred with FGR had a reduced GR number in lymphocytes due to a splice deletion near exon 6 (Karl et al. 1993). The females with this FGR type showed hirsutism, menstrual irregularities, and acne due to the ACTH-induced hypersecretion of androgens (Lamberts et al. 1992a). One unrelated patient was found who suffered from fatigue and resistance to dexamethasone suppression, and a young FGR boy showed sexual precocity. These cases were described in detail in excellent reviews (Stratakis et al. 1994, Malchoff and Malchoff 1995, Bronnegfu-d and Carlstedt-Duke 1995, Bronneg&-d et a]. 1996). Although only few kindreds with severe inherited receptor deficits have been described, recent data suggest a much more frequent occurrence of generalized mutations in the GR gene without apparent clinical symptoms (J.W. Koper and S.W.J. Lamberts personal communication). Also, inherited defects in chaperone proteins (for example, HSP90), receptor-associated transcrip-
tion factors, glucocorticoid response element (GRE), or regulatory regions of GR target genes could similarly result in mild deficits in receptor function. It is conceivable, however, that such receptor variants produce cortisol dysfunction that may become harmful only during conditions of chronic stress. Preliminary observations indeed suggest signs of feedback resistance in healthy subjects at genetic risk for depression (Holsboer et al. 1995). Of course, proof of this thesis must await the actual manifestation of depression in these individuals. Although severe inherited deficits in GRs resulting in asymptomatic hypercorticism seem a rare disorder in humans, some species such as guinea pigs, prairie voles, and new-world monkeys have receptor deficits by nature. The guinea pig shows generalized mutations in the GR gene, causing reduced affinity of GR for cortisol. The ACTH molecule is changed to a much more potent “super agonist” (Keightly and Fuller 1994). There is normal circadian variation in HPA activity but ACTH and cortisol are circulating at a much higher level. Apparently, the strongly elevatedset point in HPAactivity in these animals has proved to be an adequate adaptation,given their evolutionary success (Funder 1994). Even the complete lack of GR is not incompatible with life, as was recently found in transgenic mice homozygous for targeted disruption of the GR gene (Cole et al. 1995). The mice were generated by introduction of a null mutation in the mouse GR gene and subsequent targeting of embryonic stem cells. Although most GR-deficient mice die shortly after birth owing to respiratory failure, a few (5%-IO% of the newborns) survive. These survivors show a complete lack of adrenal medulla and, thus, of circulating epinephrine. They have greatly enlarged adrenal cortices and very high ACTH and corticosterone levels. Neither the homozygous nor the heterozygous animals show signs of adrenal insufficiency or Cushing’s syndrome, respectively.A closer look at the behavioral studies revealed a memory deficit (M.S. Oitzl personal communication), and an electrophysiological survey (M. Joels personal communication) revealed disturbances in ion regulation, which can be ascribed to lack of brain GRs. In conclusion, FGR in humans is a rare disorder characterized by a general-
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Figure2. The molecular basis of glucocorticoid resistance. Glucocorticoids (red triangles)pass the cell membrane and bind to the glucocorticoid receptor (GR) at the carboxy-terminal steroid-binding site (indicated in yellow). Upon binding of glucocorticoids, the receptor is translocated to the nucleus. (A) Transactivation of steroid receptor: DNA-binding site of the receptor (indicated in orange) recognizes specific DNA sequences, the glucocorticoid response elements (GREs). This binding will direct the transcription of genes containing GREs. (B) Transrepression: activated GRs may also repress the activity of other transcription factors by direct protein-protein interaction. (C) Transcription factors (TF) (indicated in dark blue): TFs such as activating-protein I (AP-1) and nuclear factor-KB (NFKB) are normally activated by inflammatory processes or stress and, as the GR, bind to specific DNA sequences (TF sites, indicated in gray), thus directing the transcription of specific target genes. Glucocorticoid resistance develops when the action of TFs is insufficiently restrained by GRs. Two alternative splice variants of the GR are generally expressed as the GRci and the GR~ (see light yellow box). The GR~ does not bind glucocorticoids, but it may interfere with transcription activation of the GRw Several naturally occurring point mutations leading to amino acid substitutions and one deletion have been characterized in the GRa(seelight yellow box). Especially, mutations in the steroid-binding domain (indicated in darkyellow) will lead to aberrant steroid-binding capacities and, thus, to malfunctioning of process of transactivation (situation A). In addition, as part of this GR domain and the, domains are also involved in the binding of other TFs, transrepression (situation B) is also severely affected. This malfunctioning of the GR in both transactivation and transrepression may facilitate the development of glucocorticoid resistance.
ized GR deficit that does not result in glucocorticoid-dependent pathological processes in view of adaptation in the set point of HPA activity. However, GR vari-
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ants may exist that only under conditions of high demand promote dysregulation in glucocorticoid action and increase risk of disease.
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Acquired Glucocorticoid Resistance
Tissue-specific glucocorticoid resistance generally does not produce a compensatory rise in circulating cortisol level. Such local resistance may be acquired during inflammato~ processes, which then explains the need for treatment with potent synthetic glucocorticoids. For instance, two categories of glucocorticoid-resistant asthma patients were distinguished (Barnes and Adcock 1993, Kam et al. 1993). The rare type II form of resistance is irreversible. It is characterized by a reduced number of GRs and normal binding affinity, suggesting some resemblance to FGR. Yet, type I resistance is characterized by reduced affinity and increased binding capacity of GR in T-lymphocytes. In culture, this GR defect is reversible, but it is maintained upon coincubation with interleukin (IL)-2 and IL-4. The action of these cytokines, therefore, may be causal to in-
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adequate GR function. Likewise, GR deficits may also be associated with susceptibility to other inflammatory or immune disorders (for example, rheumatoid arthritis or multiple sclerosis) due to locally evoked disturbances by inflammatory mediators (Kam et al. 1993). How can local steroid resistance be acquired? One cause may be tissue-specific receptor mutation, but evidence for this was so far only found in tumors of a patient suffering frOITINelson syndrome (Stratakiset al. 1994).Another cause may be alternativesplicing of the GR gene. A hGR~ variant was found widely distributed in addition to the common hGR (hGRa) (Bamberger et al. 1995and 1996). Glucocorticoids do not bind to GR@. Cotransfection of COS-7 monkey kidney tumor cells with both isofonns revealed that the GR~ form is transcriptionallyinactive. GR~, however, blocks the effect of GR-mediated transactivationin a concentration-dependent manner, although it does not seem to interfere with transrepression (Bamberger et al. 1996). In newworld monkeys, overexpression of the GRp variant is observed, which could explain their glucocorticoid feedback resistance. Cidlowski et al. (1996) recently observed that the GR~ variantwas preferentiallyinduced over GRa after exposure to cytokines. A second category of factors inducing steroid resistance is indicated by recent data on crosstalk between nuclear receptors and membrane signaling cascades. One possibility is the change in receptor properties through enzymatic modifications, for example, phosphorylation in response to peptides and transmitters (Zhang et al. 1994). Another possibility (Figure 2) is the interaction of GR with nonliganded transcription factors such as activatingprotein I (API), cAMP response element-binding protein (CREB), or nuclear factor KB(NFKB)(Pfahl 1993).These proteins are activated by membrane-signalingpathwaysin response to inflammatory, immune, and stress mediators (for example, cytokines, excitatory amino acids, and biogenic amines). GRs repressthe generally positive effects of AP1, CREB, and NFKB on gene transcription either directly via composite GREs or indirectly by protein–protein interaction. Inadequate repression by GR is characteristic for steroid resistance during inflammatory and immune disorders. Glucocorticoid resistance may also be related to inTEM vol. 8, No. 1, 1997
creased GR polymorphism in the T2 do-
few days in elevated corticosteroid levels
main (Barnes and Adcock 1993). Mutations in this receptor domain impair interaction with transcription factors,
during the circadian rise and in response to stress, CRH mRNA, ACTH, and basal trough corticosterone are not changed, but the adrenocortical sensitivity to ACTH is increased (Van Haarst et al. 1996b). Third, impairment of adrenocortical function is a possible way by which the balance of excitatory and inhibitory signals in the PVN is changed. For instance, if rats are treated with the steroid-synthesis inhibitor cyanoketone, their corticosterone response to stress is facilitated (Akana and Dallman 1992, Dallman et al. 1992, Dallman 1993). Alternatively, reset of feedback sensitivity occurs when the input from multiple sensory signaling pathways converging on CRH neurons becomes disproportionate (Figure 1). This occurs with physical stressors, for example, evoked by infection, trauma, inflammation, respiratory distress, or hemorrhage. These stressors activate brain stem aminergic neurons, which stimulate CRH and VP synthesis directly through al adrenergic receptors (Plotsky 1991). Disproportionate input to CRH neurons can also be due to cognitive stimuli, which may become particularly potent chronic stressors under conditions of anxiety, uncertainty, lack of control, or poor predictability of upcoming events, either real or imagined. The elevated glucocorticoid levels caused by such chronic physical and psychological stressors produce tolerance for elevated glucocorticoids through downregulation of GRs in the CRH/VP neurons (De Kloet 1991). The lower GR number would allow a reduced magnitude of the glucocorticoid signal and, as consequence, a further dysregulation of the HPA axis. The anatomicalsubstratefor processing of cognitive stimuliis the limbic-forebrain circuit~ including the hippocampus, a brain structure involved in regulation of mood, learning, and memory processes (Chan-PalayandKohler 1989).Input from locus coeruleus noradrenergic, raphe serotonergic, and mesocortical dopaminergic neurons modulates the processing and appraisalof environmentalinformation in these higher brain circuits. Importantly a rise in glucocorticoids, in turn, promotes stress-inducedactivationof these serotonergic, dopaminergic, and noradrenergic neurons in the brain stem and increases the sensitivityof limbic-forebrain areas to the aminergic inputs (McEwen 1987).
whereas the binding to DNA or steroids is not hampered. In conclusion, glucocorticoid resistance is acquired by local changes in the receptor state, the local generation of different receptor variants, or altered crosstalk of GR with other signaling pathways. Possibly, inherited defects in the GR may facilitate the acquisition of resistance.
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GlucocorticoidFeedback Resistancein Neural Stress Response Circuitry
Glucocorticoid resistance acquired in CRH neurons becomes manifest if feedback control of stress-induced activation of CRH neurons fails. The principal feature of glucocorticoid resistance in CRH neurons is the same as seen with, for example, asthma or arthritis: The balance between GR function on the one hand and the drive of converging signal transduction pathways and transcription factors on the other hand is disturbed (Figure 1). However, the site of resistance, that is, the very neurons where feedback control is regulated, is crucial. The resistance to glucocorticoid feedback in CRH neurons causes increased HPA activity and produces hypercorticism. As an unfortunate consequence, the rest of the body and the brain, including the neural stress response circuitry, suffers from glucocorticoid overexposure. One way in which the balance just described can be disturbed is when a local GR deficit exists. This can be an inherited property, as is demonstrated in the recently engineered transgenic mouse line with brain-selective reduced expression of the GR. Such mice display hypercorticism, cognitive impairment, and metabolic disturbances that in many aspects resemble the symptoms of Cushing’s syndrome (Barden et al. 1995). Second, it can also be.acquired, as is shown by a pharmacological approach using chronic daily administration of 200 mg/day of the antiglucocorticoid RU 486 (Lamberts et al. 1992b). If RU 486 is infused continuously (100 rig/day) into the brain ventricles of rats, the chronic blockade of brain GR results within a
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of
HPA activity
PATHOLOGY Figure 3. Mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are colocalized in hippocampal neurons. Their relative activation depends on the circulating corticosteroid level. During physiological conditions, MRs are considerably occupied even with low corticosteroid levels, as occurs during the circadian trough; GRs are onfy partly occupied (upper panel). When corticosteroid levels rise, for example, after acute stress, most of the GRs will be activated in addition to the MRs (middle panel). Cellular properties of hippocampal neurons carrying MRs and GRs are modulated by steroid receptor activation. Predominant MR activation results in stable amino acid–mediated transmission, small Ca influxes, and small aminergic responses. In general, this is a favorable condition for neuronal stability. With additional GR activation, amino acid responses are reduced, and Ca influx is large. At a short scale, this may serve to reverse stress-induced hippocampal excitation. The MR- and GRmediated cellular effects have consequences for functions in which the hippocampus plays an important role, such as cognition and (transsynaptically) the regulation of hypothalamic– pituitary-adrenal (HPA) activity. Chronic hypercorticism associated with glucocorticoid feedback resistance leads to chronic activation of MRs and GRs (lower panel). GR-mediated events such as reduction of inhibitory amino acid responses and increased Ca influx, which at a short time scale are beneficial, now increase vulnerability to neurodegenerative processes. At least in part because of these detrimental effects, cognitive impairment occurs, and the process of steroid resistance is (transsynaptically) exacerbated. These include the direct aminergic input to the CRH/VP neurons, as well as the
indirect route to these CRH neurons via the hippocampus. By this reinforcing
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mechanism, the feedback resistance at the
level of the CRH neurons is increasin~y aggravated. The ensuing hypercorticism and arninergic sensitization potentially
enhances the organism’s vulnerability to brain disorders such as addiction (Piazza et al. 1991) and depression (Chrousos 1995, Holsboer and Barden 1996). A single traumatic life event is often sufficient to trigger this vicious circle in glucocorticoid-amine interactions and to precipitate stress-related disorders. The effect of psychosocial distresscan be demonstrated in rats after a decisive defeat (Bohus et al. 1987) or even after exposure to one session of inescapable footshocks (Van Dijken et al. 1993).After these single traumatic events, feedback resistance slowly evolves over a period of several weeks. The most persistent effects are, however,observed after an early life experience. Three-day-old rats deprived of their mother for 24 h display as adults, hypercorticism and downregulation of GR.s in the hypothalamic PVN. The deprived animals also display increased nigrostriatal- and tubero-infundibular dopamine reactivity (Rots et al. 1996a). There are, however, sex and strain differences in the effect of early life experience, and the time point and the duration of the maternal separation procedure also modulates development of the adult phenotype. Interestingly, maternal separation restricted to 15 min per day causes the opposite effect. Such socalled handled animals have a reduced emotional and adrenocortical reactivity (Levine 1994, Meaney et al. 1988). The outcome of mother–pup interaction is further superimposed on genotype. For instance, rat lines genetically selected for extreme differences in susceptibility to apomorphine showed developmental changes in HPA reactivity, which preceded the divergence in dopamine phenotype (Rots et al. 1996b). In conclusion, the set point of HPA activity is programmed by genotype but can be changed to another level by early life events. This reset of HPA activity evolves slowly and may lead to a vicious circle of enhanced input to CRH neurons, feedback resistance, and hypercorticism. These inputs originate from brain stem and limbic circuits.
.
Role of Hippocampus in Feedback Resistance
As discussed earlier here, the functional outcome of limbic (hippocampal) circuitry is important for the activity of CRH neurons. What adds to the com-
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plexity of this influence of higher brain structures on stress physiology is that the hippocampus itself forms a prime target for corticosteroid hormones. Elevated corticosteroid levels, which are the basis as well as a consequence of feedback resistance in the hypothalamus, will therefore indirectly, via the hippocampus, determine the nature of the influence exerted by higher brain structures. How do they accomplish this? Hippocampal cells express MRs and GRs (De Kloet 1991). Cortisol and corticosterone bind with a 10-fold higher affinity to MRs than to GRs. Because of this, high-affinity MRs are already predominantly occupied by low basal corticosteroid levels. GRs become activated additionally to MRs when steroid levels rise, for example, after stress and toward the circadian peak. It was shown that MR and GR activation affect local signal transduction differently (Joels and De Kloet 1992 and 1994). Therefore, the relative MRIGR occupation in a hippocampal cell determines how cellular events and the hippocampal networks in which the cells participate are affected (Figure 3). These hippocampal networks in turn play a role in mood and cognition (Oitzl and DeKloet 1992, McEwen and Sapolsky 1995) and also in fear and anxiety (Korte et al. 1995). They indirectly regulate CRH neurons via a poorly understood transsynaptic pathway involving an inhibitory GABA-ergic input to the PVN (Swanson 1991). MR expression is high in hippocampus and other limbic structures but virtually absent from CRH neurons. Studies in rats have demonstrated that low levels of corticosterone acting through these extrahypothalamic MRs are already sufficient to suppress HPA activity. In adrenalectomized rats,basal-troughACTHlevelswere obtained, if corticosterone levels are kept constant at about 100 nM (= 0.8 nM free steroid) via replacementwith slow-release corticosterone pellets. Circadian rises in HPAactivitywere blocked when sufficient corticosterone was provided to activate GRs, but the occupation of MRs was indispensablefor this effect (Bradbury et al. 1994). A variety of experimental conditions have also demonstrated the significance of hippocampal MR in control of the HPA tone. First, pharmacological blockade with MR antagonists increased basal and stress-induced HPA activity (Ratka TEM vol. 8, No. 1, 1997
Figure4. 3H-Corticosterone binding in the dorsal hippocampus of interleukin (IL)-1 treated rats. Seven-day adrenalectomized rats were injected intracerebroventricular (icv) with vehicle (left) or 100 ng IL-1 (right). After 2 h the animals were given subcutaneous injections of tracer 3H-corticosterone. Three hours after the injection, IL-1 or vehicle (that is, 1 h after injection of the radiolabeled tracer) animals were killed, the brain was cut, and the sections exposed to autoradiographic film. The experiment demonstrates that tracer amounts of 3H-corticosterone are retained selectively by the mineralocorticoid receptor (MR). IL-1 impairs steroid retention by reducing the affinity of MR. The figure is modified &orn Schobit~ et al. (1994). et al. 1989, Bradbuv et al. 1994). Second, in females, the cyclic increase of HPA activity at the evening of proestrus occurs when the high estrogen and progesterone levels impair MR function (Carey et al. 1995). Third, rat strains with high hippocampal MR expression (for example, Lewis rats) show lower HPA activity (Oitzl et al. 1995). Fourth, aged individuals have generally reduced MR expression and increased HPA activity (Van Eekelen et al. 1995). Finally, tricyclic antidepressants increase hippocampal MRs and decrease HPA activity (Yau et al. 1995, Holsboer and Barden 1996). The previous examples concern physiological events, but in the pathophysiological realm, MR function also affects HPA activity. IL-1 administration causing hypercorticism and fever reduces affinity of corticosterone to MRs in hippocampus (Figure 4). The impaired MR function is paralleled by a pronounced increase in set point of HPA activity (Schobitz et al. 1994). Cytokine-induced resistance was also noted in GRs in lymphocytes during septic shock (Molijn et al. 1995) and, as mentioned previously, in T-lymphocytes of asthma patients. It is not known whether this effect of cytokines involves a direct influence on the receptor or is achieved indirectly via the elevated temperature. The output of the hippocampus activates an inhibito~ GABA-ergic input to the CRH neurons, which is maintained via MRs. Hippocampal GR activation produces opposite effects (Joels and De Kloet 1994) and counteracts the inhibitory control over CRH neurons. Moreover, chronic high glucocorticoid levels
impair cognitive processes and behavioral adaptation. The authors propose that the effects of chronic psychological stress in the development of glucocorticoid feedback resistance are reinforced, at a later stage, by elevated corticosteroid levels acting via MRs and GRs in the hippocampus. In summary, these observations show that MR-controlled input from extrahypothalamic structures is critical for the tone of the HPA activity. It remains to be shown if dysregulation of the HPAaxis is a consequence of impaired action at higher brain centers or if it primarily develops at the level of the PVN. Relevant to the situation of glucocorticoid resistance is that excess of corticosteroids impairs cognitive performance and signaling in the hippocampus, which indirectly also affects CRH synthesis (Wolkowitz 1994, McEwen and Sapolsky 1995, De Kloet and Joels 1996). .
Conclusion
A fundamental question in stress research is how or at what time glucocorticoid hormones stop facilitating adaptation and start increasing vulnerability to damage. The present review has demonstrated that acquired feedback resistance is one criterion to discriminate “good” from “bad” steroid action. Such resistance develops when excitatory influences override glucocorticoid feedback and reset the tone of the HPA axis. This condition is representative for a range of stress-related disorders, including depression and anorexia. Alternatively supersensitivity to glucocorticoid feedback also exists. This
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condition of enhanced feedback results in lower tone of HPA activity and, thus, hypocorticism and reduced 24-h cortisol production. Reduced glucocorticoid exposure due to enhanced negative feedback efficacy was recently also recognized as a pathological condition. It is characteristic for posttraumatic stress disorder (Yehuda 1996). Chronic fatigue syndrome (Chrousos 1995) and fibromyalgia (Griep et al. 1993) also show features of secondary adrenocortical deficiency of central origin. Increasing evidence suggests that the primary defect in these disorders of the stress-response system is related to the function of MRs and GRs in the brain. Future research may elucidate whether polymorphisms in MRs and GRs predispose for stress-related disorders, particularly during chronic psychosocial stress. Knowledge of the properties of hippocampal MRs and its splice variants is essential, as it is this receptor type that regulates the tone of the HPA activity and the neuronal processes in higher brain regions underlying perception and cognitive performance. It will be a challenge to unravel how these higher brain centers communicate with the endocrine system, and what defects in MRs and GRs disturb an effective dialogue with corticosteroid hormones. This would allow the identification of dysregulated genes as potential targets for treatment of stress-related disorders.
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Bamberger CB, Schulte HM, Chrousos GP: 1996. Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev 17:245–261. Barden N, Reul JMHM, Holsboer F: 1995. Do anti-depressantsstabilize mood on the hypothalamic-pituitary-adrenocortical system? TrendsNeurosci 18:6-14. Barnes PJ, Adcock I: 1993. Anti-inflammatory actions of steroids: molecular mechanisms. TrendsPharmacol Sci 14:436-441.
The support by the Netherlands Organization for Scientific Research (NWO) is gratefully acknowledged. We thank Ms. Ellen M. Heidema for editorial assistance.
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