The hypothalamic-pituitary-adrenal axis adapts to periods of chronic or repeated stress. We have now investigated whether there is any differential effect of repeated immobilization stress on CRH and arginine vasopressin (AVP) gene transcription in the hypothalamic paraventricular nucleus (PVN), using probes for both intronic and exonic sequences of the AVP and CRH genes. Daily restraint for 13 days had no significant affect on basal corticosterone level, CRH heteronuclear RNA (hnRNA), CRH messenger RNA (mRNA), AVP hnRNA, or AVP mRNA. After the final episode of acute restraint, on day 14, there was a rapid increase in plasma corticosterone and AVP hnRNA level in the parvocellular subdivision of the PVN, a slower increase in AVP mRNA level in the parvocellular subdivision of the PVN, but no significant change in either CRH hnRNA or CRH mRNA in the PVN. The increase in AVP hnRNA and mRNA was specific to the parvocellular PVN, because there was no change in either transcript in the magnocellular cells of this nucleus. This isolated response is in marked contrast to naive rats, which show a predominant CRH hnRNA and mRNA response, and infers that part of the adaptation to repeated stress results from a down-regulation of CRH gene responsiveness with maintenance or even a compensatory increase in the AVP gene response.