Stress-responsive neurons of the hypothalamic paraventricular nucleus (PVN) show functional plasticity and adapt to repeated restraint (RR) stress. To investigate whether neuronal adaptation to the homotypic stress also affects their response to a heterotypic stressor, we used in situ hybridization with intronic and exonic probes to measure primary transcript (hnRNA) and messenger RNA (mRNA) levels for CRH and vasopressin (VP) in the PVN of control and RR rats after the heterotypic stress of i.p. hypertonic saline injection (ipHS). Two weeks of daily restraint blunted plasma corticosterone and parvocellular CRH, but not VP, transcript responses to a further restraint episode. IpHS increased circulating corticosterone in both groups, but levels were higher in RR rats. CRH hnRNA increased within 15 min and returned to baseline by 1 h in both naive and RR rats. CRH mRNA increased more slowly in both groups, peaking at 2 h, with RR rats showing greater responses at this time. Parvocellular VP hnRNA reached a peak 2 h after ipHS in naive rats, but more rapidly (1 h) and to higher levels in RR rats. The number of parvocellular neurons expressing VP hnRNA increased approximately 5-fold after ipHS in both groups. Basal VP mRNA levels and the number of parvocellular cells expressing VP mRNA were elevated in RR rats. Both ipHS and naive rats showed an increase in VP mRNA transcripts after ipHS, with RR rats showing greater levels at 2 and 4 h. Magnocellular cells in both PVN and supraoptic nuclei showed increases in VP hnRNA within 15 min. The data demonstrate VP responses in parvocellular neurons of both control and RR rats, whereas profound inhibition of CRH transcription is selective for the homotypic stressor with CRH responsiveness to the heterotypic stress preserved or increased.