PubMed · 15432849
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1950. ACTH and cortisone (compound E).. https://pubmed.ncbi.nlm.nih.gov/15432849/
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Stress is a part of every life to varying degrees, but individuals differ in their stress vulnerability. Stress is usefully viewed from a biological perspective; accordingly, it involves activation of neurobiological systems that preserve viability through change or allostasis. Although they are necessary for survival, frequent neurobiological stress responses increase the risk of physical and mental health problems, perhaps particularly when experienced during periods of rapid brain development. Recently, advances in noninvasive measurement techniques have resulted in a burgeoning of human developmental stress research. Here we review the anatomy and physiology of stress responding, discuss the relevant animal literature, and briefly outline what is currently known about the psychobiology of stress in human development, the critical role of social regulation of stress neurobiology, and the importance of individual differences as a lens through which to approach questions about stress experiences during development and child outcomes.
We previously have described molecular mechanisms converging at the Nur response element-signal transducer and activator of transcription (STAT) composite site responsible for synergistic activation of the proopiomelanocortin (POMC) gene promoter by leukemia inhibitory factor (LIF) and CRH. In this study, we asked how glucocorticoids (GC), the physiological negative regulators of POMC gene expression, modulate this synergism. In the corticotroph cell line AtT-20, the response of the wild-type promoter to LIF+CRH was barely inhibited by GC, whereas a distal promoter subregion (-414/-293) encompassing the Nur response element-STAT site and devoid of the negative GC-responsive element located in the proximal domain, displayed a cooperative response to LIF+dexamethasone (DEX) and LIF+CRH+DEX treatments. LIF+CRH-stimulated ACTH secretion was also inefficiently inhibited by DEX in the same cell line. This study was focused thereafter on LIF+DEX cooperativity, which may be responsible, on the wild-type promoter, for lack of negative regulation by DEX of the LIF+CRH synergy. The STAT1-3 low-affinity site, in the context of the (-414/-293) subregion of the POMC promoter, was found necessary and sufficient for transcriptional synergism between activated GC receptor (GR) and STAT1-3. Moreover the activities of reporters specific for STAT1-3 or GR were reciprocally enhanced by DEX or LIF. Single and sequential chromatin immunoprecipitations revealed 1) a STAT-dependent corecruitment of coactivators after LIF and LIF+DEX stimulation and 2) a more lasting recruitment of both STAT3 and GR in the same enhanceosome on the endogenous POMC promoter after LIF+DEX joint stimulation than after the single one. Such events may be responsible for a lack of repressive property of GR unmasked on the whole POMC promoter during LIF+CRH stimulation and may contribute to the tonicity of the hypothalamic-pituitary-adrenal axis during inflammatory-infectious diseases.
Animal studies have shown that blockade of central mineralocorticoid receptors (MR) has anxiolytic effects and impairs several aspects of cognitive function. No study to date assessed the effects of MR blockade on anxiety and cognitive function in humans. In the present study, 16 healthy young men were treated either with placebo or with 300 mg spironolactone, a MR-antagonist, at 1100, 1330, and 1630 hours in a balanced cross-over design with the two study conditions being 1 week apart. At 1500 hours, the panic symptoms provoking compound cholecystokinin-tetrapeptide (CCK-4) was administered i.v. on both occasions and panic symptoms were assessed. We measured plasma ACTH and cortisol between 1300 and 1900 hours and assessed cognitive function between 1800 and 1900 hours. CCK-4 elicited panic symptoms and increased ACTH and cortisol secretion in both conditions. Intensity of panic symptoms after CCK-4 was not different between spironolactone and placebo. Spironolactone significantly impaired selective attention and delayed recall of visuospatial memory, and diminished set shifting/mental flexibility on a trend level. Pretreatment with spironolactone led to higher baseline cortisol levels compared to placebo whereas no differences in stimulated cortisol, baseline ACTH, and stimulated ACTH emerged. Blockade of MR with spironolactone increases baseline cortisol secretion and impairs cognitive function but has no effect on experimentally induced panic symptoms in humans, for the study design and dosage of spironolactone used. The domains of cognitive function that are impaired after blockade of MR in men, that is, selective attention, visuospatial memory, and mental flexibility/set shifting appear to be remarkably similar to those described in animal studies.