Regulation of Proopiomelanocortin Gene Transcription during Single and Repeated Immobilization Stress

Abstract

We have previously reported that repeated immobilization produces persistent activation of the hypothalamic-pituitary-adrenocortical axis in rats. In an attempt to assess whether any adaptational responses occur at the pituitary level, we examined the detailed time courses of proopiomelanocortin (POMC) gene transcription in the anterior pituitary (AP) in comparison with those of corticotropin-releasing hormone (CRH) gene transcription in the hypothalamic paraventricular nucleus (PVN) during single and repeated immobilization using both intronic and exonic probes. During single immobilization, there was a robust and rapid increase in both CRH heteronuclear RNA (hnRNA) in the PVN and POMC hnRNA in the AP, together with a slower increase in CRH mRNA, but no significant increase in POMC mRNA. Single immobilization also caused significant increases in the plasma concentrations of both ACTH and corticosterone. Daily immobilization for 6 days increased the basal levels of CRH hnRNA and CRH mRNA in the PVN and POMC mRNA in the AP. Both CRH hnRNA and POMC hnRNA responded rapidly to a final episode of acute immobilization on day 7, whereas the peak values of CRH hnRNA and POMC hnRNA after 15 min of the final stress were smaller than those during single immobilization. In contrast to single stress, CRH mRNA did not change significantly, whereas POMC mRNA robustly increased after the final immobilization on day 7. Plasma ACTH increased to a similar degree to single stress, but its initial increase at 5 min was significantly higher than that during single immobilization. The increase in the plasma corticosterone concentration was higher during final immobilization than during single stress. These results suggest that, in response to the hypothalamic drive during repeated immobilization stress, pituitary corticotrophs are capable of upregulating the basal and stress-induced POMC mRNA levels via increased efficiency of the posttranscriptional processing of the hnRNA and/or increased mRNA stability.