SYNAPTIC INTERACTION BETWEEN MEDULLARY RESPIRATORY NEURONS DURING APNEUSIS INDUCED BY NMDA-RECEPTOR BLOCKADE IN CAT

1. Termination of inspiration is an essential component of respiratory rhythm generation and its perturbation can result in apneusis, i.e. significant prolongation of inspiratory activity. In an effort to further analyse inspiratory termination mechanisms, we studied the postsynaptic events in respiratory neurones during apneustic respiratory periods, and compared them to normal respiratory cycles. 2. Experiments were performed in pentobarbitone-anaesthetized, paralysed, thoracotomized cats ventilated with a constant volume or a cycle-triggered constant pressure pump. Apneusis, separated by normal cycles, was induced as follows: the animal was ventilated by a cycle-triggered pump that normally inflated the lungs during the inspiratory burst of phrenic nerve discharge. The NMDA-receptor blocker MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-iminemaleate] (0.3-0.7 mg/kg) was administered intravenously, and, for designated breaths, inflation of the lungs was withheld during neural inspiration. 3. Membrane potential trajectories of forty-one late expiratory (E-2) and eight postinspiratory (PI) neurones of the caudal ventral respiratory group were analysed before and/or after MK-801 administration, during normal and apneustic periods. 4. Before MK-801 administration, withholding lung inflation caused modest (10-20%) lengthening of the inspiratory period; after MK-801 administration, withholding inflation caused apneusis. Provided that the lungs were inflated during the inspiratory phase, the temporal pattern of phrenic nerve, recurrent laryngeal nerve and membrane potential trajectories of E-2 and PI neurones were not significantly altered by MK-801. Apneusis following NMDA-receptor blockade produced consistent changes in the synaptic activation patterns of E-2 neurones. In particular, the slow late inspiratory-related depolarization pattern of E-2 neurones was consistently retarded during apneustic inspiratory phases when compared to normal inspiratory phases. This was due to continuation of Cl-mediated synaptic inhibition of E-2 neurones. Superior laryngeal nerve stimulation stopped apneusis and sustained membrane hyperpolarization of E-2 neurones similar to lung inflation. 5. During the plateau phase of apneusis, correlated 10-20 Hz oscillations could be observed in the integrated phrenic and recurrent laryngeal nerve activities as well as in the membrane potential of E-2 neurones. 6. We conclude that: (i) the prolonged inhibition of E-2 neurones during apneusis is indicative of the process responsible for the prolongation of the inspiratory phase. (ii) Synaptic interactions between medullary respiratory neurones and spinal respiratory motoneurones producing burst patterns of motor output do not require NMDA-receptor-mediated pathways. (iii) Pathways used by pulmonary and laryngeal afferents to terminate inspiration also do not require NMDA-receptor-mediated function. (iv) NMDA-receptor controlled pathways necessary for inspiratory termination seem to be activated in the absence of lung inflation and to involve the pontine respiratory group of neurones. (v) MK-801-induced apneusis affects the interaction between early-inspiratory and late-inspiratory neurones resulting in oscillations.