N-methyl-D-aspartate (NMDA) receptors mediate afferent peripheral chemoreceptor response in the conscious rat

Exogenous L-glutamate increases ventilation (V_E) in a dose-dependent manner. In anesthetized dogs, reduced V_E responses to hypoxia follow NMDA receptor blockade. To further examine NMDA receptor role in respiratory control, we measured in concious, freely-behaving rats, V_E responses to hypercapnia (5% CO), hypoxia (10%O₂), and increasing iv sodium cyanide (Cyan) doses, before, and after administration of a non-competitive NMDA receptor antagonist, i.V. 3 mg/kg dizocilpine maleate (MK-801), A significant V_E reduction occurred after MK-801 injection, and was primarily due to marked tidal volume decreases, with declines in both inspiratory and expiratory durations. Hypercapnic V_E responses were minimally affected after MK-801 (p - NS). In contrast, hypoxic V_E responses were markedly attenuated (p < 0.0001). Similarly, Cyan doses associated with significant V_E increases were 5 μg/kg and 50 μg/kg in preand post-MK-801 conditions, respectively. Thus, 1-log shifts to the right of individual dose-response curves occurred with MK-801 (p < 0.001). Furthermore, even at Cyan doses eliciting significant V_E changes, MK-801 -treated animals had smaller V_E increases (P ± 0.01). We conclude that centrally-located neurons expressing NMDA glutamate receptors mediate synaptic relays of peripheral chemoreceptor afferent traffic.