Glucocorticoid negative feedback selectively targets vasopressin transcription in parvocellular neurosecretory neurons

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.