To identify molecular targets of corticosteroid negative feedback effects o
n neurosecretory neurons comprising the central limb of the hypothalamo-pit
uitary-adrenal (HPA) axis, we monitored ether stress effects on corticotrop
in-releasing factor (CRF) and arginine vasopressin (AVP) heteronuclear RNA
(hnRNA) expression in rats that were intact or adrenalectomized (ADX) and r
eplaced with corticosterone (B) at constant levels ranging from nil to peak
stress concentrations. Under basal conditions, relative levels of both pri
mary transcripts varied inversely as a function of plasma B titers. In resp
onse to stress, the kinetics of CRF hnRNA responses of intact and ADX rats
replaced with low B were similar, peaking at 5 min after stress. By contras
t, intact rats showed a delayed AVP hnRNA response (peak at 2 hr), the timi
ng of which was markedly advanced in ADX/low B-replaced animals (peak at 5-
30 min). Transcription factors implicated in these responses responded simi
larly. Manipulation of B status did not affect the early (5-15 min) phospho
rylation of transcription factor cAMP-response element-binding protein (CRE
B) but accelerated maximal Fos induction from 2 hr after stress (intact) to
1 hr (ADX). Assays of binding by proteins in hypothalamic extracts of simi
larly manipulated rats toward consensus CRE and AP-1 response elements supp
orted a role for the stress-induced plasma B increment in antagonizing AP-1
, but not CRE, binding. These findings suggest that glucocorticoid negative
feedback at the transcriptional levels is exerted selectively on AVP gene
expression through a mechanism that likely involves glucocorticoid receptor
interactions with immediate-early gene products.