The effects of diencephalic lesions on respiratory responses to intra-arterially infused adenosine (ADO) were determined in chronically catheterized fetal sheep (>0.8 term). These studies were designed to test the hypothesis that the inhibitory effects of ADO on fetal breathing, like those of hypoxia, are mediated by the parafascicular nuclear complex (Pf) of the posteromedial thalamus. ADO inhibited breathing [control (C): 26 +/- 2.6, ADO: 4 +/- 1 min/h] in normal fetuses and in a fetus with a lesion that virtually destroyed the thalamus but left intact most of Pf. Neuronal lesions in the diencephalon, produced by injecting ibotenic acid, abolished the inhibitory effects of ADO on breathing (C: 31 +/- 5.1, ADO: 30 +/- 4.5 min/h) when the lesions encompassed Pf or the sector immediately rostral to Pf that retained the capacity to regulate hypoxic inhibition. Smaller lesions created by the insertion of needles also eliminated the depressant effects of ADO when disruptions were within Pf or a rostral component of the thalamic cortical activating system. It is concluded that 1) a medial thalamic sector is critically involved in ADO-induced apnea and 2) ADO-dependent and ADO-independent mechanisms mediate hypoxic inhibition.