Involvement of excitatory amino acids in neurotransmission of inspiratory drive to spinal respiratory motoneurons

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Abstract
The role of excitatory amino acids in the transmission of bulbospinal respiratory drive to spinal motoneurons was investigated in the in vitro and in vivo spinal cord of the rat. In vitro studies were performed with a preparation of neonatal rat brain stem and spinal cord that spontaneously generates rhythmic respiratory drive to spinal respiratory motoneurons. This in vitro system allowed examination of the effects of pharmacological agents on spinal motoneuron activity, without perturbing the activity of bulbospinal neurons transmitting the respiratory drive. The amplitude of spontaneous motor discharge in spinal ventral roots containing phrenic and intercostal motor axons was reduced in a dose-dependent manner by antagonists to excitatory amino acids acting at NMDA receptors [D,L-2-amino-5-phosphonovaleric acid (D,L-AP5)] and non-NMDA receptors [kynurenic acid, gamma-D- glutamylglycine, gamma-D-glutamyltaurine, and L- and D,L-2-amino-4- phosphonobutyric acid (L-AP4,D,L-AP4)]. The order of potency of the antagonists for complete block of the motor output was L-AP4 greater than D,L-AP4 greater than kynurenic acid greater than gamma-D- glutamylglycine greater than D,L-AP5 greater than or equal to gamma-D- glutamyltaurine. Amino acid uptake inhibitors augmented the spontaneous motoneuron activity, further confirming the involvement of endogenous excitatory amino acids in transmission of respiratory drive. The results obtained in vitro with AP4, kynurenic acid, and amino acid uptake inhibitors were confirmed in vivo by bathing segments of the rat spinal cord in situ with solutions containing antagonists and uptake inhibitors. The present results suggest that an important component of the neurotransmission of bulbospinal respiratory drive involves endogenous excitatory amino acids acting at AP4-sensitive sites and other non-NMDA (quisqualate/kainate) receptors. The bulbospinal-spinal respiratory motoneuron synapse may provide a convenient model synapse in the spinal cord for detailed analysis of mechanisms underlying excitatory amino acid-mediated synaptic transmission of motor drive.