Blockade of NMDA receptor-channels by MK-801 alters breathing in adult rats

The role of N-methyl-D-aspartate (NMDA) receptor-channel activation in the production of respiratory pattern was studied by administration of the NMDA receptor-channel blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801, 1-3 mg/kg, i.v.) to anesthetized adult rats. This dose of MK-801 blocked the excitatory effects of NMDA (applied iontophoretically) on brainstem respiratory neurons. The predominant respiratory response to systemic MK-801 administration was an increase in inspiratory duration and a decrease in amplitude of diaphragm electromyogram and phrenic nerve discharge. Effects on inspiratory timing and amplitude were most pronounced when the rats were vagotomized. Significant changes in arterial blood gases and pH after systemic MK-801 administration in spontaneously breathing rats (vagi intact or cut) indicated that ventilation was depressed by NMDA receptor-channel antagonism. Respiratory timing changes in response to systemic MK-801 administration differed between two rat strains studied. Breathing patterns resembling apneusis, i.e., with irregular inspiratory durations prolonged 2- to 30-fold, occurred in 60% of the vagotomized, spontaneously breathing Sprague-Dawley rats and none of the Wistar rats. Thus, the breathing pattern in Sprague-Dawley rats is more sensitive to interference with NMDA-mediated mechanisms. We propose that respiratory pattern generation and transmission of rhythmic respiratory drive are mediated by synergistic activation of NMDA and non-NMDA receptors at brainstem and spinal cord sites.