Regulation of corticotropin-releasing factor type 1 (CRF1) receptor messenger ribonucleic acid in the paraventricular nucleus of rat hypothalamus by exogenous CRF

The present study sought to examine the effects of intracerebroventricular (icv) administration of corticotropin-releasing factor (CRF) on the expression of CRF, receptor messenger RNA (mRNA) within the hypothalamus as determined by quantitative in situ hybridization histochemistry. Adult male Sprague-Dawley rats were stereotaxically implanted with guide cannulae directed towards the right lateral ventricle. After 8-10 days of recovery, either 10 mu l CRF (5 mu g) or vehicle solution was injected into the lateral ventricle over a 2-min period. The rats were then deeply anesthetized at 15, 60, and 180 min after icv injection, transcardially perfused, and their brains cut into 30-mu m coronal sections. Brain sections were then processed using standard radioactive in situ hybridization histochemistry revealing the expression of the CRF, receptor mRNA. Low to moderate basal levels of CRF, receptor transcript were observed in several regions of the forebrain. However, the hybridization signal for the mRNA encoding the CRF, receptor was barely detectable in the paraventricular nucleus of the hypothalamus (PVN) of vehicle-injected rats. In contrast, 180 min after icv administration of CRF, a significant increase in CRF, receptor transcript was measured specifically in the PVN, despite having virtually any hybridization signal before 180 min. This increase in the level of receptor transcription by CRF was restricted to the type 1 receptor subtype because the hybridization signal for the CRF(2 alpha) receptor mRNA was unaffected in the brain regions in which it was located. Moreover, we confirmed previous findings of a CRF-induced neuronal activation of parvocellular neurosecretory cells of the PVN, as assessed by c-fos mRNA expression. This neuronal activation induced by exogenous CRF was also associated with a rapid and strong induction of CRF heteronuclear RNA selectively in the rat PVN, a phenomenon abolished by a pretreatment with a CRF receptor antagonist. These results provide evidence that elevated levels of central CRF may trigger CRF, receptor transcription selectively in the PVN. This positive feedback of CRF on its own receptor may represent a functional adaptation of the hypothalamic-pituitary-adrenal axis in response to stress.