Respiratory responses evoked by blockades of ionotropic glutamate receptors within the Botzinger complex and the pre-Botzinger complex of the rabbit

The respiratory role of excitatory amino acid (EAA) receptors within the Botzinger complex (BotC) and the pre-Botzinger complex (pre-BotC) was investigated in alpha-chloralose-urethane anaesthetized, vagotomized, paralysed and artificially ventilated rabbits by using bilateral microinjections (30-50 nL) of EAA receptor antagonists. Blockade of both N-methyl-d-aspartic acid (NMDA) and non-NMDA receptors by 50 mm kynurenic acid (KYN) within the BotC induced a pattern of breathing characterized by low-amplitude, high-frequency irregular oscillations superimposed on tonic phrenic activity and successively the disappearance of respiratory rhythmicity in the presence of intense tonic inspiratory discharges (tonic apnea). KYN microinjections into the pre-BotC caused similar respiratory responses that, however, never led to tonic apnea. Blockade of NMDA receptors by D(-)-2-amino-5-phosphonopentanoic acid (D-AP5; 1, 10 and 20 mm) within the BotC induced increases in respiratory frequency and decreases in peak phrenic amplitude; the highest concentrations caused tonic apnea insensitive to chemical stimuli. Blockade of non-NMDA receptors by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1, 10 and 20 mm) within the BotC produced only less pronounced increases in respiratory frequency. Responses to D-AP5 in the pre-BotC were similar, although less pronounced than those elicited in the BotC and never characterized by tonic apnea. In the same region, CNQX provoked increases in respiratory frequency similar to those elicited in the BotC, associated with slight reductions in peak phrenic activity. The results show that EAA receptors within the investigated medullary subregions mediate a potent control on both the intensity and frequency of inspiratory activity, with a major role played by NMDA receptors.