Stress-induced sensitization of the hypothalamic-pituitary adrenal axis is associated with alterations of hypothalamic and pituitary gene expression.
We have previously reported that inescapable tail shock (IS) produces persistent changes in hypothalamic-pituitary-adrenal (HPA) axis function. These changes are manifest as an elevation in basal corticosterone (CORT) levels, a sensitization of adrenocorticotropin hormone (ACTH) and CORT responses to subsequent challenge, and a failure of dexamethasone to suppress both the ACTH and CORT responses to a subsequent challenge. The experiments presented here examine IS-induced alterations in the responsiveness of the HPA axis, particularly at the level of the anterior pituitary. The data presented show that adrenalectomy does not abolish the IS-induced sensitization of the HPA axis, suggesting that the sensitization is not solely caused by a defect in glucocorticoid negative feedback. Analysis of gene expression in the anterior pituitary revealed that IS exposure persistently elevated basal levels of proopiomelanocortin (POMC; the precursor to ACTH) mRNA and sensitized the POMC hnRNA and c-fos mRNA response to a subsequent challenge. Analysis of gene expression in the parvocellular division of the paraventricular nucleus of the hypothalamus (pPVN) after IS exposure revealed that basal levels of corticotropin-releasing hormone (CRH) mature mRNA are elevated and the c-fos mRNA response to a subsequent challenge is enhanced. Finally, a blunted in vitro ACTH response to CRH challenge is observed after IS exposure. These data suggest that the ultimate source of the IS-induced sensitization is not the anterior pituitary and implicate an increased drive on the anterior pituitary from the pPVN.
O'Connor
Kevin A
KA
Center for Neuroscience and Department of Psychology, University of Colorado at Boulder, Boulder, CO 80309-0345, USA.
Ginsberg
Abigail B
AB
Maksimova
Elena
E
Wieseler Frank
Julie L
JL
Johnson
John D
JD
Spencer
Robert L
RL
Campeau
Serge
S
Watkins
Linda R
LR
Maier
Steven F
SF
D000315:Adrenalectomy / Q000379:methods; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002452:Cell Count / Q000379:methods; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000494:pharmacology / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D015870:Gene Expression / Q000502:physiology*; D005786:Gene Expression Regulation; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D017403:In Situ Hybridization / Q000379:methods; D008297:Male; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D010913:Pituitary-Adrenal System / Q000503:physiopathology*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000528:radiation effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000528:radiation effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013312:Stress, Physiological / Q000503:physiopathology*; D013997:Time Factors
D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone