Urocortin 1 (Ucn1) neurons, most abundantly expressed in the Edinger-Westphal nucleus (E-WN), respond to various acute challenges. In a recent study, we found that acute ether stress resulted in the strongest activation of E-WN Ucn1 cells, as revealed by immunohistochemistry for Fos (often used as a marker for neuronal activation). Although the acute stress responsiveness of E-WN Ucn1 neurons has been widely studied, the activation pattern of Fos in these neurons in response to repeated challenges has not yet been investigated. Therefore, we quantitatively studied Fos activation in E-WN neurons and measured Ucn1 mRNA levels in E-WN neurons after acute and chronic ether stress in mice. Acute stress resulted in a robust Fos response and an increase in Ucn1 mRNA as compared to non-stressed mice. In the chronic stress paradigm, Fos expression was unchanged, whereas after 2 and 3 weeks of daily ether exposure Ucn1 mRNA expression had strongly declined in the E-WN. Fos and Ucn1 mRNA were co-expressed in E-WN neurons in both acutely and chronically stressed animals. This paper is the first to demonstrate that Ucn1 mRNA-expressing neurons in the E-WN show a non-habituating Fos response to a chronic homotypic ether challenge that also resulted in a reliable down-regulation of E-WN Ucn1 mRNA levels vs. acutely stressed animals. Based on these results, we propose that the E-WN-Ucn1 system represents a novel stress adaptation pathway, which may play an important role in coping with chronic challenges.