This study addressed the hypotheses that exposure to chronic hypoxia (CH) and chronic hypercapnia (CHC) would modify the acute hypercapnic ventilatory response in the cane toad (Rhinella marina; formerly Bufo marinus or Chaunus marinus) and its regulation by NMDA-mediated processes. Cane toads were exposed to 10 days of CH (10% O(2)) or CHC (3.5% CO(2)) followed by acute in vivo hypercapnic breathing trials, conducted before and after an injection of the NMDA-receptor channel blocker, MK801 into the dorsal lymph sac. CH, CHC and MK801 did not alter ventilation under acute normoxic normocapnic conditions. CH blunted the increase in breathing frequency during acute hypercapnia while CHC had no effect. The effect of CH on breathing frequency was mediated by a decrease in the number of breaths per breathing episode. Neither CH nor CHC altered breath area (volume). MK801 augmented breathing frequency (via an increase in breaths per episode) and total ventilation during acute hypercapnia in control toads and toads exposed to CH; there was no effect of MK801 on the increase in breathing frequency or total ventilation, during acute hypercapnia in toads exposed to CHC. The results indicate that CH and CHC differentially alter breathing pattern. Furthermore, they indicate an absence of NMDA-mediated glutamatergic tone during normoxic normocapnia but that NMDA-mediated processes attenuate the increase in breathing frequency during acute hypercapnia under control conditions and following CH but not following CHC. Given that MK801 was administered systemically, the effects could be acting anywhere in the reflex pathway from CO(2)-sensing to respiratory motor output.