title: Chronic psychosocial stress results in sensitization of the HPA axis to acute heterotypic stressors despite a reduction of adrenal in vitro ACTH responsiveness.
abstract: Although chronic psychosocial stress is often accompanied by changes in basal hypothalamo-pituitary-adrenal (HPA) axis activity, it is vital for a chronically-stressed organism to mount adequate glucocorticoid (GC) responses when exposed to acute challenges. The main aim of the present study was to test whether this is true or not for the chronic subordinate colony housing (CSC, 19 days) paradigm, an established and clinically relevant mouse model of chronic psychosocial stress. As shown previously, CSC mice are characterized by unaffected morning and decreased evening plasma corticosterone (CORT) levels despite enlarged adrenals, suggesting a maladaptive breakdown of adrenal functioning. Plasma CORT levels, determined by repeated blood sampling via jugular vein catheters, as well as relative right adrenal CORT content were increased in CSC compared with single-housed control (SHC) mice in response to acute elevated platform (EPF, 5min) exposure. However, in vitro stimulation of adrenal explants with physiological and pharmacological doses of ACTH revealed an attenuated responsiveness of both the left and right adrenal glands following CSC, despite mRNA and/or protein expression of melanocortin 2 receptor (Mc2r), Mc2r accessory protein (MRAP), and key enzymes of steroidogenesis were not down-regulated. Taken together, we show that chronic psychosocial stressor exposure impairs in vitro ACTH responsiveness of both the left and right adrenal glands, whereas it increases adrenal responsiveness to an acute heterotypic stressor in vivo. This suggests that an additional factor present during acute stressor exposure in vivo rescues left and right adrenal ACTH sensitivity, or itself acts as CORT secretagogue in chronically stressed CSC mice.
authors.affiliation: Department of Behavioural and Molecular Neurobiology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Uschold-Schmidt
authors.forename: Kewir D
authors.initials: KD
authors.lastname: Nyuyki
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Füchsl
authors.forename: Inga D
authors.initials: ID
authors.lastname: Neumann
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Reber
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000311:Adrenal Glands / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis; D002908:Chronic Disease; D004291:Dominance-Subordination; D006854:Hydrocortisone / Q000032:analysis; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D044103:Receptor, Melanocortin, Type 2 / Q000096:biosynthesis; D013315:Stress, Psychological / Q000097:blood / Q000503:physiopathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C551627:MRAP2 protein, human; D044103:Receptor, Melanocortin, Type 2; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone