The medial prefrontal cortex (mPFC) phasically regulates neural activity in the amygdala during extinction of fear conditioning and in the paraventricular nucleus of the hypothalamus (PVN) during various kinds of stress. Whether the mPFC also tonically regulates limbic an hypothalamic nuclei during times of low fear and stress is not known, but was tested in the present study. Rats received bilateral electrolytic lesions of the mPFC (both prelimbic and infralimbic areas) or sham lesions and were allowed to recover for 7 days. Rats were then sacrificed 1 hour after being transported to the laboratory and the brains were removed. In situ hybridization for the immediate early gene, egr-1, and corticotropin-releasing hormone (CRH) mRNA was performed in the PVN, bed nucleus of the stria terminalis (BNST), and the central nucleus (CeA) and lateral nucleus (Lat) of the amygdala. No changes between sham and lesioned groups were found with regards to egr-1 mRNA expression in any of the areas investigated. Significant decreases in CRH mRNA expression were found in the CeA following the mPFC lesion, as well as significant increases in CRH mRNA in the Lat. CRH mRNA expression in the PVN or BNST did not change. The data suggest that the mPFC does not exert inhibition or excitation of immediate-early gene activity during times of basal, low-stress conditions. The CRH results seem to implicate that the mPFC does not, as a whole, exhibit simply inhibitory effects towards stress; however, because the mPFC has at least two regions, the prelimbic and infralimbic, that inhibit and activate limbic areas, respectively, the conclusion should be taken with caution. Further research with separate lesions of these two regions is warranted.