The relative role of N-methyl-D-aspartate (NMDA) and non-NMDA receptors in synaptic responses of neurons in caudal nucleus tractus solitarii (cNTS) was delineated by immunohistochemical and electrophysiologic experiments in rats. Double immunohistochemical staining in in vivo experiments revealed that ~80% of cNTS neurons that showed Fos-like immunoreactivity induced by baroreceptor activation were generally also immunoreactive to non-NMDA receptor subunits GluR1 or GluR2. On the other hand, only 20% of Fos-labeled cNTS neurons showed immunoreactivity to NMDA receptor subunits NMDAR1 or NMDAR2. Stimulation of the ipsilateral solitary tract at suprathreshold intensity in slice preparations induced Fos expression in the cNTS and evoked either a single action potential or a complex synaptic response consisting of an initial action potential followed by a secondary slow depolarization. In a majority (70%) of cNTS neurons that exhibited the complex synaptic response, both the initial and secondary components were eliminated reversibly by 6- cyano-7-nitroquinoxaline-2,3-dione (20 μM). This non-NMDA antagonist also inhibited the single action potential manifested by the other population of cNTS neurons. On the other hand, only the secondary slow depolarization was blocked by D(-)-2-amino-5-phosphonopentanoic acid (250 μM) or potentiated by NMDA (1.7 μM). Our results suggested that NMDA and non-NMDA receptors are involved differentially in the synaptic responses of cNTS neurons. Non-NMDA receptors may be distributed predominantly on a majority of the second-order cNTS neurons that may receive primary baroreceptor afferent inputs. On the other hand, NMDA receptors are located primarily on higher-order neurons, which may be connected reciprocally with the second-order cNTS neurons.