Mechanisms Underlying the Increased Plasma ACTH Levels in Chronic Psychosocially Stressed Male Mice

Abstract

Mice exposed to chronic subordinate colony housing (CSC, 19 days), an established paradigm for chronic psychosocial stress, show unaffected basal morning plasma corticosterone (CORT) concentrations, despite enlarged adrenal glands and an increased CORT response to an acute heterotypic stressor. In the present study we investigate the mechanisms underlying these phenomena at the level of the pituitary. We show that both basal and acute stressor-induced (forced swim (FS), 6 min) plasma adrenocorticotropic hormone (ACTH) concentrations, the number of total and corticotroph pituitary cells, and relative protein expression of pituitary mineralocorticoid receptor and FK506-binding protein 51 was increased in CSC compared with single-housed control (SHC) mice, while relative corticotropin releasing hormone (CRH) receptor 1 (CRH-R1) and glucocorticoid receptor protein expression was down-regulated. Relative pituitary pro-opiomelanocortin and arginine vasopressin (AVP) receptor 1b (AVPR-1b) protein expression, FS (6 min)-induced ACTH secretion in dexamethasone-blocked mice, and the number of AVP positive magnocellular and parvocellular neurons in the paraventricular hypothalamic nucleus (PVN) was unaffected following CSC. Taken together, the data of the present study indicate that 19 days of CSC result in pituitary hyperactivity, under both basal and acute heterotypic stress conditions. Although further studies have to assess this in detail, an increased number of pituitary corticotrophs together with unaffected relative pituitary AVPR-1b and decreased CRH-R1 protein expression following CSC suggests that pituitary hyperdrive is mediated by newly formed corticotrophs that are more sensitive to AVP than CRH. Moreover, our data indicate that changes in PVN AVP and negative feedback inhibition seem not to play a major role in pituitary hyperactivity following CSC.

Chronic Subordinate Colony Housing Paradigm: A Mouse Model to Characterize the Consequences of Insufficient Glucocorticoid Signaling

“…In line with what we found at the adrenal level, the increased capability of the CSC pituitary gland to produce and secret ACTH is mediated at least partly by corticotroph cell hyperplasia ( 155 ). Non-compromised functionality of those newly formed cells was suggested by comparable relative pituitary pro-opiomelanocortin protein expression between CSC and SHC mice ( 155 ).…”

“…In confirmation of this hypothesis, mice exposed to 19 days of CSC indeed show exaggerated plasma CORT concentrations, as well as an increased adrenal CORT content, when killed 5 min following termination of a mild acute heterotypic stressor (EPF) at the beginning of the light phase, despite the increase in plasma ACTH concentrations not differing from EPF-exposed SHC mice ( 142 ). Notably, when exposed to a more severe acute heterotypic stressor, i.e., 6-min of forced swimming, CSC mice even show an exaggerated ACTH response compared with SHC mice ( 155 ), likely to further enhance HPA axis reactivity toward a novel and severe enough heterotypic challenge in CSC mice. A facilitated ACTH response to a novel heterotypic challenge is thereby in line with other chronic stress studies [( 156 ); for review see ( 157 )].…”

<b>Localization of ATP-sensitive K</b>^<b>+</b><b> channel subunits in rat pituitary </b><b>gland </b>

“…Pituitary adrenocorticotropic hormone (ACTH) is an important component of the hypothalamus-pituitary-adrenal (HPA) axis, which is essential for body homeostasis and survival during stress (Stevens and White, 2010;Fuchsl et al, 2013;Uchoa et al, 2014). It is influenced by various stimuli such as cortical release hormone (CRH), and to a lesser extent, by arginine vasopressin (AVP).…”

“…It is influenced by various stimuli such as cortical release hormone (CRH), and to a lesser extent, by arginine vasopressin (AVP). It receives a negative feedback suppression of cortisol from the adrenal glands (Fuchsl et al, 2013). A patch-clamp experiment for membrane potential in single rat corticotrophs showed that CRH triggered a sustained [Ca 2+ ]i elevation and membrane depolarization for corticotrophs (Lee and Tse, 1997), and ACTH secretion was related to an increase in the L-type Ca 2+ current (LeBeau et al, 1997).…”

Vasopressin in mechanisms of stress reactions and modulation of emotion

“…У мышей, подвергнутых хроническому психосоциальному стрессу (совместному проживанию доминантных и субординантных животных), повышались уровни АКТГ и кортикостерона в плазме крови, что сочеталось с неизменной экспрессией рецепторов КТРГ 1-го типа. Полагают, что в условиях хронического психосоциального стресса АВП является основным регулятором активности ГГНС [2,20]. В условиях хронического психологического стресса у человека также зафиксированы повышенные уровни АВП и кортизола в плазме крови и в цереброспинальной жидкости [5].…”