Survival in low oxygen environments requires adaptation of sympatho-respiratory control networks located in the brainstem. The molecular mechanisms underlying adaptation are unclear. In naive animals, acute hypoxia evokes increases in phrenic (respiratory) and splanchnic (sympathetic) nerve activities that persist after repeated challenges (long-term facilitation, LTF). In contrast, our studies show that conditioning rats to chronic hypobaric hypoxia (CHH), an environment characteristic of living at high altitude, diminishes the response to hypoxia and attenuates LTF in a time dependent manner. Phrenic LTF decreases following 7 d of CHH, and both sympathetic and phrenic LTF disappear following 14 d of CHH. Previous studies demonstrated that -aminobutyric acid (GABA) is released in the brainstem during hypoxia and depresses respiratory activity. Furthermore, the sensitivity of brainstem neurons to GABA is increased following prolonged hypoxia. In this study we demonstrate that GABA_A receptor expression changes along with the CHH-induced physiologic changes. Expression of the GABA_A receptor 4 subunit mRNA expression increased 2 fold in animals conditioned to CHH for 7 d. In addition, de novo expression of and 6, a subunit normally found exclusively in the cerebellum, is observed after 14 d. Consistent with these changes, diazepam-insensitive binding sites, characteristic of GABA_A receptors containing 4 and 6 subunits, increase in the pons. Immunohistochemistry revealed that CHH-induced GABA_A receptor subunit expression is localized in regions of sympatho-respiratory control within the pons. Our findings suggest that a GABA_A receptor mediated-mechanism participates in adaptation of the sympatho-respiratory system to hypobaric hypoxia.