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Orexins/hypocretins heavily innervate the posterior division of the paraventricular nucleus of the thalamus (pPVT), which expresses both orexin receptor types. The pPVT is important for adaptations to repeated stress, particularly the ability to facilitate to novel stress after repeated stress exposure. Here, we examined how orexins acting in the pPVT regulate facilitation of hypothalamic-pituitary-adrenal (HPA) responses to novel restraint after 4 d of repeated swim stress. Blockade of orexin receptors in the pPVT with SB334867 before novel restraint did not change the facilitated HPA response. However, blockade of orexin receptors before each of four daily swim exposures prevented the facilitated ACTH and facilitated hypothalamic c-Fos response to restraint as well as the repeated swim stress-induced increase in CRH mRNA in the paraventricular hypothalamus. These results suggest that orexin actions in the pPVT during the 4 d of swim, but not during restraint, are necessary for the facilitated HPA response to heterotypic restraint. Exposure to the fourth swim produced a shift in orexin1 receptors from membrane to cytosolic fractions. OrexinA also changed the firing patterns of pPVT cells to be more responsive in repeatedly swim stressed rats compared with nonstressed rats. Together, the results suggest that orexin actions in the pPVT, mediated by orexin1 receptors, are important for the ability to adapt to repeated stress.

Orexins/Hypocretins Act in the Posterior Paraventricular Thalamic Nucleus During Repeated Stress to Regulate Facilitation to Novel Stress