MicroRNAs and osmotic regulation.
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Animals↗
Biomedical subjects
Stafford L Lightman
Publications and source records attributed to Stafford L Lightman.
Tryptophan metabolism in the central nervous system: medical implications.
The metabolism of the amino acid L-tryptophan is a highly regulated physiological process leading to the generation of several neuroactive compounds within the central nervous system. These include the aminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), products of the kynurenine pathway of tryptophan metabolism (including 3-hydroxykynurenine, 3-hydroxyanthranilic acid, quinolinic acid and kynurenic acid), the neurohormone melatonin, several neuroactive kynuramine metabolites of melatonin, and the trace amine tryptamine. The integral role of central serotonergic systems in the modulation of physiology and behaviour has been well documented since the first description of serotonergic neurons in the brain some 40 years ago. However, while the significance of the peripheral kynurenine pathway of tryptophan metabolism has also been recognised for several decades, it has only recently been appreciated that the synthesis of kynurenines within the central nervous system has important consequences for physiology and behaviour. Altered kynurenine metabolism has been implicated in the pathophysiology of conditions such as acquired immunodeficiency syndrome (AIDS)-related dementia, Huntington's disease and Alzheimer's disease. In this review we discuss the molecular mechanisms involved in regulating the metabolism of tryptophan and consider the medical implications associated with dysregulation of both serotonergic and kynurenine pathways of tryptophan metabolism.
Animals↗
The four-dimensional stress test: psychological, sympathetic-adrenal-medullary, parasympathetic and hypothalamic-pituitary-adrenal responses following inhalation of 35% CO2.
BACKGROUND: Hypercapnia is a threat to homeostasis and results in neuroendocrine, autonomic and anxiogenic responses. The inhalation of carbon dioxide (CO2) may, therefore, provide a good paradigm for exploring the pathways by which stress can lead to increased susceptibility to ill-health through physiological and psychological stress reactivity. The current study was designed, therefore, to assess the psychological and physiological responses to the inhalation of CO2. METHODS: Healthy participants (N = 24) inhaled a single vital capacity breath of a mixture of CO2 (35%) and oxygen (65%). Blood pressure and heart rate were recorded for 5 min before and after the test and blood and saliva samples were taken immediately before and 2, 10, 20 and 30 min post-inhalation for the measurement of noradrenaline, salivary and serum cortisol and salivary alpha amylase. In addition, psychosomatic symptoms were recorded immediately before and after the test. The same protocol was repeated 4-6 weeks later at the same time of day. RESULTS: A single inhalation of CO2 increased blood pressure, noradrenaline, salivary alpha amylase and psychosomatic symptoms, but decreased heart rate at both testing sessions. Analyses of salivary cortisol data revealed that 70% of the sample could be reliably classified as either responders (i.e. demonstrated a post-CO2 cortisol increase) or non-responders (i.e. responded with a decrease or no change in cortisol following CO2) at both test sessions. Responders also perceived the test to be more aversive than non-responders. CONCLUSIONS: Inhalation of 35% CO2 reliably stimulated the key mechanisms involved in the human stress response. The inter-individual differences in the reactivity of the hypothalamic-pituitary-adrenal axis were also related to differences in the perception of the test.
Administration, Inhalation↗
Lipopolysaccharide has indomethacin-sensitive actions on Fos expression in topographically organized subpopulations of serotonergic neurons.
Peripheral immune activation results in physiological and behavioral responses including changes in the level of behavioral arousal. One mechanism through which immune activation can influence these responses is via actions on brainstem neuromodulatory systems, including serotonergic systems. To investigate the effects of peripheral immune activation on serotonergic systems and behavior, and the potential role of prostanoids in mediating these effects, we compared the effects of intraperitoneal injections of lipopolysaccharide (LPS), in the presence or absence of the cyclooxygenase inhibitor indomethacin, on total plasma L-tryptophan concentrations, Fos expression in subdivisions of the brainstem raphe complex, and home cage behaviors. Peripheral LPS administration had no effect on total plasma L-tryptophan concentrations but increased Fos expression in serotonergic neurons selectively within the interfascicular (DRI) and ventrolateral (DRVL) subdivisions of the dorsal raphe nucleus 4 h following treatment; pretreatment with indomethacin blocked the LPS-induced increases in Fos expression within the DRI and DRVL. Peripheral LPS administration decreased measures of behavioral arousal including locomotion, rearing, climbing, and self-grooming; LPS administration had no effect on these behaviors in mice pretreated with indomethacin. The indomethacin-sensitive effects of LPS on Fos expression in the DRI may be due to selective activation of Type II serotonergic neurons which are largely restricted to the DRI region and have unique afferent regulatory mechanisms and behavioral correlates. Further studies of the effects of peripheral immune activation on DRI serotonergic systems may lead to a better understanding of the relationships among immune function, serotonergic systems, and behavior.
Analysis of Variance↗
Neuroendocrine and behavioural responses to CO2 inhalation in central versus peripheral autonomic failure.
Multiple system atrophy (MSA) and pure autonomic failure (PAF) represent distinct pathological models of autonomic failure in humans. We have investigated the neuroendocrine, behavioural and autonomic cardiovascular responses to the 35% CO2 challenge. Nine patients with MSA, nine with PAF and five control subjects received a single breath of 35% CO2. Peripheral autonomic failure (i.e., PAF) was associated with significantly lower resting noradrenaline levels. All groups demonstrated a significant pressor response to CO2. In controls, the mean pressor response was +60.2 mm Hg, which was significantly smaller in both the PAF (+26.8 mm Hg, P < 0.01) and MSA (+18.3 mm Hg, P < 0.001) patients. In addition, the onset of the response was significantly delayed in both MSA (140.2 s) and PAF (154.2 s) patients compared with controls (32.4 s, P = 0.04 and P = 0.03, respectively). Noradrenaline levels increased only in controls. Central autonomic impairment (i.e., MSA) was associated with lower cortisol release (+8.8% in MSA compared with +35.2% in control and +23.7% in PAF) and fewer somatic symptoms of emotional arousal. Both MSA and PAF exhibit marked sympathetic autonomic impairment, however, residual (albeit differing) sympathetic pathways can still maintain a partial cardiovascular response. A central autonomic lesion, however, also appears to be associated with blunting of both cortisol and emotional responses to this stress paradigm.
Aged↗
An investigation of hypothalamic-pituitary-adrenal axis hyperactivity in anorexia nervosa: the role of CRH and AVP.
We hypothesised that hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in anorexia nervosa (AN) is associated with (a) elevated arginine vasopressin (AVP) activity and (b) enhanced pituitary sensitivity to AVP, as it is in depressive illness. 16 Healthy women and 18 women with active AN participated in a combined dexamethasone (DXM)/corticotrophin releasing hormone (CRH) challenge test and an AVP challenge test. This combination of tests is designed to assess the functional contribution of AVP to HPA axis activity. 10 of the active AN group repeated participation after weight gain. The cortisol response to AVP was reduced by 138% in the active AN group, suggesting an impairment of pituitary sensitivity to AVP, which began to normalise with weight gain. The cortisol and adreno-corticotrophin (ACTH) responses to the DXM/CRH test were not significantly enhanced in the active AN group, suggesting that there was no elevated endogenous AVP activity augmenting the response to CRH in AN. Weight gain was associated with blunting of the endocrine response to the DXM/CRH test, which may have been related to rising oestrogen levels. Thus, contrary to the hypotheses, we did not find (a) evidence of upregulated AVP activity or (b) enhanced pituitary sensitivity to AVP in AN. These findings suggest that the mechanism of HPA axis hyperactivity differs in depression and AN, with greater involvement of AVP in depressive disorder and perhaps more reliance on CRH to drive the axis in AN. The powerful anorexigenic effect of CRH could contribute to the severity of weight loss associated with AN.
Adolescent↗
Gonadal steroid modulation of stress-induced hypothalamo-pituitary-adrenal activity and anxiety behavior: role of central oxytocin.
Intracerebroventricular administration of oxytocin reduces anxiety behavior and hypothalamo-pituitary-adrenal (HPA) responses to stress in female rats. Similar changes are seen in late-pregnant rats, and oxytocin-sensitive pathways may mediate these effects. This study investigated anxiety behavior and stress responses using a gonadal steroid model of late pregnancy, which is known to increase endogenous oxytocin expression. Compared with continuous progesterone treatment, 3-d withdrawal of progesterone after 11-d treatment of ovariectomized rats with estradiol and progesterone resulted in increased binding of the oxytocin receptor ligand [(125)I]d(CH(2))(5)[Tyr(Me)(2),Thr(4),Tyr-NH(2)(9)]ornithine vasotocin in selective forebrain regions, including the ventrolateral septum and ventromedial hypothalamus. Behavior in the elevated plus-maze indicated that progesterone withdrawal had an anxiolytic effect, and this was associated with lower levels of c-fos mRNA expression in the ventral hippocampus, an area previously shown to be sensitive to oxytocin. In other groups of animals, the plasma corticosterone response to a psychological stress (10 min of 114 dB white noise) was significantly attenuated by this steroid manipulation. Furthermore, simultaneous infusion of the selective oxytocin receptor antagonist desGlyNH(2), d(CH(2))(5)[Tyr(Me)(2),Thr(4)]OVT during the period of progesterone withdrawal reversed this attenuation of noise-induced HPA activation, indicating a role for endogenous oxytocin in this effect. Thus, mimicking the steroid profile of late pregnancy leads to a reduction in anxiety behavior and attenuates HPA activity induced by mild stress. These effects appear to be mediated through the involvement of central oxytocin neurotransmission.
Adrenal Glands↗
Corticotrophin-releasing factor type 2 receptor-mediated suppression of gonadotrophin-releasing hormone mRNA expression in GT1-7 cells.
Corticotrophin-releasing factor (CRF) released during stress has been implicated in the suppression of the hypothalamo-pituitary-gonadal (HPG) axis, especially the gonadotrophin-releasing hormone (GnRH) pulse generator, the central neural regulator of pituitary LH and FSH secretion, resulting in reproductive dysfunction. The gonadal steroid 17beta-oestradiol (E2) has been shown to enhance CRF- and stress-induced suppression of pulsatile LH secretion. In the present study, we investigated the potential direct action of CRF on GnRH neurones by using GT1-7 cells, an established GnRH cell line. Furthermore, we investigated the modulatory influence of E2 on the effects of CRF and expression of CRF type 2 receptors (CRF-R2). Expression of CRF-R2 in the GT1-7 cells was detected by reverse transcription-polymerase chain reaction (RT-PCR). CRF produced a dose-dependent suppression of GnRH mRNA expression, an effect reversed by the selective CRF-R2 antagonist, astressin2-B (Ast2-B). E2 combined with CRF resulted in a greater suppression of GnRH expression compared with either treatment alone. E2 also increased CRF-R2 expression. These results demonstrate for the first time expression of CRF-R2 in the GT1-7 cells and suggest that CRF may directly regulate GnRH gene expression, an effect mediated, at least in part, by CRF-R2. They also raise the possibility that up-regulation of CRF-R2 may contribute to the sensitising influence of E2 on CRF- and stress-induced suppression of the GnRH pulse generator.
Animals↗
Characterisation of c-Fos expression in the central nervous system of mice following right atrial injections of the 5-HT3 receptor agonist phenylbiguanide.
Cardiopulmonary receptors relay signals to the central nervous system via vagal and spinal visceral afferents. To date there are no detailed topographical studies in mice indicating the distribution of central neurones activated following stimulation of cardiopulmonary afferents. In anaesthetised mice, we injected the 5-HT(3) receptor agonist phenylbiguanide (PBG), a drug that is known to stimulate cardiopulmonary afferent C-fibres, into the right atrium of the heart and mapped c-Fos expression within specific regions of the central nervous system. Intra-atrial injection of PBG produced a reflex cardiorespiratory response including a pronounced bradycardia and a respiratory depression. Using immunohistochemical detection of the protein product of the immediate-early gene c-fos, we mapped the brain regions affected by cardiopulmonary 5-HT(3) receptor stimulation. Within the nucleus of the solitary tract (nTS) of PBG-injected mice, we detected an increased number of c-Fos-positive nuclei in the dorsolateral and gelatinous parts at the level of the area postrema (-7.48 mm bregma) but not at more rostral or caudal levels (-7.76, -7.20, -6.84 and -6.36 mm bregma) relative to vehicle-injected control mice. In addition, c-Fos expression in the crescent part of the lateral parabrachial nucleus was decreased in PBG-injected mice whereas no significant differences were detected between PBG-injected and control mice in the number of c-Fos-positive nuclei in the dorsal part of the lateral parabrachial nucleus. PBG injections had no significant effects on the number of c-Fos-positive catecholaminergic neurones within the C1/A1, C2/A2, A5, A6 and A7 cell groups. Likewise, PBG injections had no significant effects on c-Fos expression in other central regions involved in cardiorespiratory control or cardiorespiratory reflexes (selected non-catecholaminergic nuclei in the medulla and midbrain periaqueductal gray, the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala). Identification of specific regions of the nTS complex involved in relaying signals from afferent cardiopulmonary C-fibres to the central nervous system will be useful for future studies aimed at understanding neural mechanisms underlying cardiopulmonary reflexes and physiological responses to cardiopulmonary disease.
Animals↗
Are tuberomammillary histaminergic neurons involved in CO2-mediated arousal?
An increase in arousal in response to hypercapnia [elevated arterial PCO2 (partial pressure of CO2) levels] during awake or sleep states is an important component of mechanisms designed to maintain acid-base homeostasis. Since central histaminergic neurons are crucial for maintaining waking states and vigilance, a nonresponsive or dysfunctional histaminergic system could contribute to the lack of arousal in response to hypercapnia in some sleep-related disorders [e.g., sudden infant death syndrome (SIDS) and Ondine's curse]. Therefore, the present study attempted to determine if histaminergic neurons display functional responses to acute exposure to hypercapnic gas (i.e., gas with elevated CO2 concentrations). Healthy adult male rats were placed in flow cages during the light cycle, or inactive phase, and exposed to either atmospheric air or to environmental CO2 concentrations increasing from baseline up to 20% CO2 over a 5-min period. The expression of the protein product of the immediate-early gene c-fos was used as a measure of functional cellular responses within subpopulations of histaminergic neurons. Among the histaminergic subgroups (E1-E5), only the ventral tuberommamillary nucleus (VTMn)/E2 cell group showed significant increases in c-Fos expression following brief exposure to hypercapnic gas. These data are consistent with the hypothesis that histaminergic neuronal cell groups are heterogeneous and are involved in physiological and/or behavioral responses to acute hypercapnic challenge, potentially increasing vigilance during active waking and awakening from sleep during hypercapnic states.
Animals↗
Acute hypercarbic gas exposure reveals functionally distinct subpopulations of serotonergic neurons in rats.
Although increasing evidence suggests that anatomically defined subpopulations of serotonergic neurons have unique stress-related functional properties, the topographical distribution of the serotonergic neurons involved in responses to stress-related stimuli have not been well-defined. Inspiration of air containing elevated concentrations of carbon dioxide (CO(2); hypercarbic gas exposure) at high concentrations activates both hypothalamic-pituitary-adrenal axis and sympathetic responses in rats and humans. In order to determine the effects of acute hypercarbic gas exposure on subpopulations of topographically organized serotonergic neurons, conscious adult male rats were placed in flow cages and exposed to either atmospheric air or increasing environmental CO2 concentrations (from baseline concentrations up to 20% CO2) for 5min. The presence of immunoreactivity for the protein product of the immediate-early gene c-fos was used as a measure, at the single cell level, of functional cellular responses within subpopulations of serotonergic, noradrenergic and adrenergic neurons. Rats exposed to hypercarbic gas had increased numbers of c-Fos/tryptophan hydroxylase immunoreactive (ir) and c-Fos/tyrosine hydroxylase-ir neurons in specific topographically organized subdivisions of brainstem nuclei, compared to control rats. Within serotonergic cell groups (B1-B9), the most striking effects occurred in a subpopulation of large, multipolar serotonergic neurons within the ventrolateral periaqueductal grey and ventrolateral part of the dorsal raphe nucleus, a region implicated in serotonin-dependent suppression of stress-induced sympathetic outflow and serotonin-dependent inhibition of 'fight or flight' behaviour. These findings have important implications for understanding the role of serotonergic systems in the modulation of stress-related physiology and behaviour and stress-related neuropsychiatric disorders.
Adrenalectomy↗
Lipopolysaccharide has selective actions on sub-populations of catecholaminergic neurons involved in activation of the hypothalamic-pituitary-adrenal axis and inhibition of prolactin secretion.
Immune activation results in adaptive neuroendocrine responses, including activation of the hypothalamic-pituitary-adrenal axis, which are dependent on the integrity of medullary catecholaminergic (CA) systems. In contrast, although specific roles of pontine, midbrain, and hypothalamic CA systems in neuroendocrine function have been described, the functional roles of these CA systems in modulating neuroendocrine function during immune responses have not been investigated. We have, therefore, investigated the effects of immune activation on the various CA systems of the central nervous system (CNS) and explored this relationship with changes in plasma corticosterone and plasma prolactin. Male BALB/c mice were injected with lipopolysaccharide (LPS, 500 microg/kg i.p.) and 2 h later cardiac blood was taken and mice were perfused with fixative. Immunostaining procedures were performed using antibodies raised against c-Fos and tyrosine hydroxylase, a marker of CA neurons, and detailed topographical analysis of the CA systems within the CNS was performed. LPS-injected mice had increased concentrations of plasma corticosterone and decreased concentrations of plasma prolactin compared with vehicle-injected controls. LPS-injected mice had increased numbers of c-Fos-positive CA neurons within the medullary (A1, A2, C1, C2), pontine (A6) and midbrain (A10) cell groups when compared with vehicle-injected controls. Among hypothalamic CA cell groups, LPS had differential effects on the numbers of c-Fos-positive CA neurons in topographically organised subdivisions of the arcuate nucleus (A12). Changes in plasma prolactin concentrations correlated with the numbers of c-Fos-positive CA neurons within the area postrema, the medullary CA cell groups, the medial posterior division of the arcuate, and the zona incerta. The present study identifies topographically organised, anatomically distinct CA systems that are likely to modulate some of the neuroendocrine responses to immune activation, and may provide novel targets for the relief of symptoms associated with illness and disease.
Animals↗
Role of corticotropin-releasing factor receptor-2 in stress-induced suppression of pulsatile luteinizing hormone secretion in the rat.
Corticotropin-releasing factor (CRF) has been implicated as an important mediator of stress-induced inhibition of reproduction. The role of specific CRF receptor subtypes in this effect is unknown, and in the current study, we investigated the role of the CRF-R2 receptor in stress-mediated suppression of pulsatile LH section. Ovariectomized rats with sc 17beta-estradiol capsules were implanted with intracerebroventricular (i.c.v.) and i.v. cannulae. Blood samples (25 microl) were collected every 5 min for 5 h for LH measurement. Central administration of urocortin II (0.24, 2.4, 24, or 240 nmol, i.c.v.), which selectively binds to CRF-R2, resulted in a dose-dependent suppression of LH pulses. Restraint stress (1 h) induced a profound suppression of pulsatile LH secretion and astressin2-B, a selective CRF-R2 antagonist (28 nmol i.c.v., 10-min prerestraint), was effective in blocking this inhibitory response. These findings suggest that CRF-R2 mediates, at least in part, restraint stress-induced inhibition of LH pulses and may play a pivotal role in the normal physiological response of stress-induced suppression of the hypothalamic GnRH pulse generator and hence the reproductive system.
Animals↗
Oxytocin attenuates stress-induced c-fos mRNA expression in specific forebrain regions associated with modulation of hypothalamo-pituitary-adrenal activity.
We reported previously that the neuropeptide oxytocin attenuates stress-induced hypothalamo-pituitary-adrenal (HPA) activity and anxiety behavior. This study sought to identify forebrain target sites through which oxytocin may mediate its anti-stress effects. Ovariectomized, estradiol-treated rats received intracerebroventricular infusions of oxytocin (1 or 10 ng/hr) or vasopressin (10 ng/hr), and the patterns of neuronal activation after restraint stress were determined by semiquantitative mapping of c-fos mRNA expression. Oxytocin administration significantly attenuated the release of ACTH and corticosterone and the increase in corticotropin-releasing factor mRNA expression in the hypothalamic paraventricular nucleus (PVN) in response to 30 min restraint. Restraint also induced the expression of c-fos mRNA in selective regions of the forebrain, including the PVN, paraventricular thalamic nucleus, habenula, medial amygdala, ventrolateral septum (LSV), most subfields of the dorsal and ventral hippocampus, and piriform and endopiriform cortices. In most cases, this level of gene expression was unaffected by concomitant administration of oxytocin. However, in the PVN, LSV, and throughout all subfields of the dorsal hippocampus, restraint evoked no detectable increase in c-fos mRNA in animals treated with either dose of oxytocin. Vasopressin had no effects on either HPA axis responses or neuronal activation in response to restraint, indicating that the effects were highly peptide selective. These data show that central oxytocin attenuates both the stress-induced neuroendocrine and molecular responses of the HPA axis and that the dorsal hippocampus, LSV, and PVN constitute an oxytocin-sensitive forebrain stress circuit.
Animals↗
Stress-induced suppression of the gonadotropin-releasing hormone pulse generator in the female rat: a novel neural action for calcitonin gene-related peptide.
In addition to its role as a potent vasodilator, calcitonin gene-related peptide (CGRP) is centrally involved in a variety of stress responses, including activation of the hypothalamo-pituitary-adrenocortical axis. It is well known that stress suppresses the activity of the hypothalamic GnRH pulse generator, the central regulator of LH and FSH pulses, resulting in reproductive dysfunction. The aim of this study was to test the hypothesis that CGRP has a critical role in mediating stress-induced suppression of pulsatile LH secretion in the rat. Ovariectomized rats were implanted with intracerebroventricular and iv cannulae. Central administration of CGRP (75 pmol-1.2 nmol) into the lateral cerebral ventricle resulted in a profound, dose-dependent suppression of LH pulses, which was reversed by a CGRP receptor antagonist (CGRP(8-37),1 nmol). Although the site of action of CGRP remains to be established, the induction of c-Fos expression in the preoptic area and hypothalamic paraventricular nucleus might suggest an involvement of these brain regions. Intravenous administration of CGRP did not affect LH pulses. Coadministration (intracerebroventricular) of CGRP (400 pmol) with a CRH antagonist (alpha-helical CRF(9-41), 26 nmol) partly blocked the CGRP-induced suppression of LH pulses. Furthermore, CGRP(8-37) (1 nmol) completely blocked hypoglycemic stress-induced suppression of LH pulses. These results suggest that the suppression of pulsatile LH secretion by central administration of CGRP may be mediated in part by CRH, and that CGRP may play a pivotal role in the normal physiological response of stress-induced suppression of the hypothalamic GnRH pulse generator, and hence the reproductive system.
Animals↗
Adrenalectomy further suppresses the NT-3 mRNA response to traumatic brain injury but this effect is not reversed with corticosterone.
Fluid percussion injury (FPI) and in situ hybridisation were used to evaluate the expression of NT-3 mRNA in the hippocampus after traumatic brain injury (TBI) in adrenal-intact and adrenalectomised rats (with or without corticosterone replacement). FPI and adrenalectomy independently significantly reduced the expression of NT-3 mRNA in the dentate gyrus (DG) and CA2 region. The effects of adrenalectomy in the CA2 region were partially reversed with corticosterone. In adrenalectomised animals undergoing FPI, a further significant decrease in NT-3 mRNA was observed in the DG, but this was not reversed by corticosterone. Glucocorticoids may, therefore, play a role in the basal regulation of NT-3 in the hippocampus, but the role of glucocorticoids in the modulation of the NT-3 response to TBI is unclear.
Adrenalectomy↗
Cortisol pulsatility and its role in stress regulation and health.
One of the classic characteristics of the human stress response is the wide inter-individual variation. Although there is much current interest in the genetic and environmental contributions to these differences, studies on human subject have been sparse and characterised by methodological problems. The major factor that is rarely taken into account is the intrinsic rhythmicity of hypothalamo-pituitary-adrenal activity, not simply the classic diurnal variation but also the endogenous pulsatility which is similar to, but much less well recognized than, the rhythms found within the reproductive and growth hormone axes. In this review we propose some novel ideas relating to the importance of pulsatility both for the design of human stress-response studies and for their interpretation as well as implications for our understanding of disease.
Animals↗
Mineralocorticoid and glucocorticoid receptors and their differential effects on memory performance in people with Addison's disease.
The effects of corticosteroids on memory performance have been the subject of some controversy. Whilst many studies have shown that high levels of corticosteroids can impair memory performance, others have shown they can facilitate it. One explanation for these discrepant effects arises from the differential activation of the two types of corticosteroid receptor--the mineralocorticoid receptor (MRs) and the glucocorticoid receptor (GRs), and the function each subserves during memory formation. Studies in rats and chickens suggest that activation of the MRs is essential during sensory storage (i.e. encoding), whereas normal levels of activation of the GRs (in addition to the already activated MRs) is essential during memory consolidation and retrieval. By using a repeated measures design with nine people with Addison's disease (mean age, 37.9 years), the effects following activation of the MRs only, GRs only, and a combination of MRs/GRs, on working memory and the episodic and semantic components of declarative memory were investigated. MRs and GRs were activated using either MR specific (9 alpha fluorohydrocortisone) or GR specific (dexamethasone) exogenous steroids, respectively. The results showed that participants performed better in the Digits Backward task when both receptors were activated compared to when GRs only were activated (P<0.01). They also performed better in recall in the Hopkins Verbal Learning Test when both receptors were activated compared to when MRs only were activated (P<0.05) and GRs only were activated (P<0.01). Whilst significant effects were not consistent across memory tasks, these results lend further support to the view that balanced activation of MRs and GRs is necessary for optimal memory function in humans.
Addison Disease↗