Endogenous activation of NMDA receptors strongly contributes to the discharge patterns of canine inspiratory hypoglossal motoneurons (IHMN) in vivo

Abstract

IHMNs are essential for the maintenance of upper airway patency especially during sleep and during stimulated breathing. We studied the effect of the NMDA receptor antagonist 2-amino-5-phosphonovalerate (AP5) on the discharge patterns of single IHMNs to determine the contribution of endogenous activation of NMDA receptors to the spontaneous activity of IHMNs during moderate hypercapnia. Multibarrel micropipettes were used to record IHMN unit activity and to picoeject AP5 (500 μM) on isolated IHMNs in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs. Anatomical location, firing in phase with the phrenic nerve and response to serotonin and/or spike-triggered averaging of hypoglossal nerve activity was used to verify that the recorded neuron was an IHMN. AP5-induced changes in discharge frequency patterns were analyzed using cycle-triggered histograms. Dose-dependent effects were studied by increases in picoejection rate. Maximally effective AP5 dose rates decreased the average (SD) discharge frequency by 55 % (12), i.e. from 38 Hz (11) to 17 Hz (6) (n = 11, p < 0.001) and the peak (SD) inspiratory discharge frequency by 42 % (12), i.e. from 69 Hz (10) to 39 Hz (5) (n = 11, p < 0.001). Analysis of discharge patterns suggests 2 types of responses to AP5:1.) Parallel downward shift, suggesting a change in tonic drive. 2.) Slope change, consistent with changes in phasic drive. Glutamate, acting on NMDA receptors, supplies about half the baseline excitatory drive to IHMN during conditions of moderate hypercpania. (Support: NIH GM59234 and VA Med. Res. Funds)