Do N-methyl-D-aspartate receptors mediate synaptic responses in the mudpuppy retina?

Whole-cell recordings of amacrine and ganglion cells in the superfused retina-eyecup preparation of the mudpuppy were obtained in order to determine which excitatory amino acid receptor (EAAR) subtype mediates the synaptic responses of these neurons. All third-order retinal neurons tested were depolarized by kainic acid (KA, N-methyl-D-aspartate (NMDA), and quisqualate (QQ). The responses evoked by NMDA were blocked by the addition of D-2-amino-5-phosphonovaleric acid (D-AP5) and D-2-amino-7 phosphonoheptonoic acid (D-AP7) to the perfusate. When the actions of exogenously applied NMDA were completely blocked by D-AP5 and D-AP7, the light-evoked responses of inner retinal neurons persisted without any apparent reduction or, alternatively, a slight enhancement of the response was observed. Light-evoked responses of bipolar, amacrine, and ganglion cells associated with the On pathway were attenuated by L-AP5 in a manner similar to its lower-order homolog L-2-amino-4-phosphonobutyrate (AP4); nevertheless, L-AP5 was not an effective NMDA antagonist. Although synaptic transmission between retinal second- and third-order neurons appears to be mediated by EAARs, the NMDA receptor does not appear to play a prominent role under our experimental conditions. Nevertheless, our results suggest that the racemic mixture of AP5 should not be used as an NMDA antagonist in retinal research, due to the AP4-like actions of its L-enantiomer.     

Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat

Subcutaneous injection of formalin into the hindpaw peripheral receptive field of deep dorsal horn multireceptive (convergent) nociceptive neurones was used to produce a prolonged (1 h) activation of the cells. This chemical noxious stimulus produced a first peak of firing which lasted 10 min followed by a second peak of prolonged activity which was monitored for 50 min. gamma-D-glutamylglycine (DGG), a non-selective N-methyl-D-aspartate (NMDA) and quisqualate/kainate (non-NMDA) receptor antagonist was applied intrathecally both as a pretreatment and after the formalin. A complete abolition of both peaks of the formalin response was produced by DGG pretreatment (1000 micrograms) (n = 4). This dose produced profound inhibition of the acute C-fibre evoked responses of the same cells. However, no inhibitions were produced when the antagonist was applied once the formalin response had developed (n = 4). The selective NMDA receptor antagonist 5-amino-phosphonovaleric acid (AP5) was administered intrathecally (250 and 500 micrograms) as a 40 min pretreatment and caused a small inhibition of the first peak but a marked dose-related reduction in the second prolonged phase (n =7). AP5 did not influence the C-fibre inputs onto the cells. The non-competitive NMDA receptor channel blockers, ketamine and MK801, were administered i.v. during the second phase of firing. Ketamine (1-8 mg/kg) caused a short-lasting but marked and dose-related inhibition of the neuronal responses to formalin (n = 11). MK801 (0.5-1 mg/kg) resulted in a prolonged inhibition of cell firing during the second phase of the response (n = 11).(ABSTRACT TRUNCATED AT 250 WORDS)     

Activation of locus coeruleus neurons by nucleus paragigantocellularis or noxious sensory stimulation is mediated by intracoerulear excitatory amino acid neurotransmission

The nucleus paragigantocellularis (PGi), located in the rostral ventrolateral medulla, is one of two major afferents to the nucleus locus coeruleus (LC). Electrical stimulation of PGi exerts a robust, predominantly excitatory influence on LC neurons that is blocked by intracerebroventricular (i.c.v.) administration of the broad spectrum excitatory amino acid (EAA) antagonists kynurenic acid (KYN) or gamma-D-glutamylglycine (DGG), but not by the selective N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-7-phosphonoheptanoate (AP7). I.c.v. injection of KYN or DGG also blocked activation of LC neurons evoked by noxious somatosensory stimuli. These results indicate that activation of LC neurons by PGi and noxious stimuli may be mediated by an EAA acting at a non-NMDA receptor in LC. In the present study, microiontophoretic techniques were used to determine the sensitivity of LC neurons in vivo to the selective EAA receptor agonists kainate (KA), NMDA and quisqualate (QUIS). Microinfusion and microiontophoresis were also used to determine whether direct application of KYN, the preferential non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) or the selective NMDA receptor antagonist 2-amino-5-phosphonovalerate (AP5) onto LC neurons blocked excitation elicited by stimulation of PGi or the sciatic nerve. The results demonstrated that individual LC neurons were robustly activated by direct application of KA, NMDA and QUIS. Iontophoretically applied KYN reduced or completely antagonized responses evoked by all 3 agonists. In contrast, iontophoretically applied AP5 strongly attenuated NMDA-evoked excitation, while KA-and QUIS-evoked responses were not affected by this agent. Furthermore, direct application of KYN or the specific non-NMDA receptor antagonist, CNQX, onto LC neurons substantially attenuated or completely blocked synaptic activation produced by PGi or sciatic nerve stimulation in nearly every LC neuron tested. Microinfusion of the selective NMDA receptor antagonist AP5 had no effect on sciatic nerve-evoked responses. These results confirm our hypothesis that activation of LC neurons from PGi is mediated by an EAA operating primarily at a non-NMDA receptor subtype on LC neurons. Furthermore, these findings provide additional support for the hypothesis that this pathway mediates at least some sensory-evoked responses of LC neurons.     

Serotonin Differentially Modulates Responses Mediated by Specific Excitatory Amino Acid Receptors in the Rat Locus Coeruleus

Microiontophoretic application of selective agonists for the three major excitatory amino acid receptors, N -methyl- d -aspartate (NMDA), quisqualate and kainate, increased the discharge rate of noradrenergic locus coeruleus (LC) neurons in vivo. NMDA activation was selectively attenuated by iontophoretic application of 2-amino-5-phosphonopentanoate (AP5), an antagonist at NMDA receptors, whereas kainate- and quisqualate-evoked responses were attenuated by both NMDA and non-NMDA antagonists iontophoresis. NMDA- and quisqualate-evoked responses were significantly decreased by co-iontophoresis of serotonin (5-HT). When the NMDA receptor-mediated component of the response to kainate was blocked with AP5 iontophoresis, 5-HT increased the response of LC neurons to kainate. These results revealed that 5-HT differentially modulates the responsiveness of LC neurons to excitatory amino acids, depending on the receptor subtypes responsible for the neuronal activation.     

Excitatory amino acid-induced release of 3H-GABA from cultured mouse cerebral cortex interneurons

A newly developed continuous superfusion model was used for studies of 3H-GABA release from cultured mouse cerebral cortex neurons. It was found that a series of excitatory amino acids (EAAs) representing all receptor subtypes evoked Ca2+- dependent release of 3H-GABA from the neurons. Quisqualate was the most potent agonist tested, with an EC50 value of 75 nM. L-Glutamate, N-methyl-D-aspartate (NMDA), and kainate showed EC50 values of 12, 16 and 29 microM, respectively. The EAA-evoked 3H-GABA release could be blocked by a series of EAA antagonists. The highly selective NMDA antagonist D-2-amino-5-phosphonovaleric acid (D-APV) was found to block NMDA responses, whereas the nonselective antagonists cis-2,3-piperidine dicarboxylic acid (PDA) and gamma-D-glutamyl-aminomethyl sulphonic acid (GAMS) blocked responses to all agonists. NMDA responses were found to be sensitive to Mg+ blockade. EAA- as well as potassium-induced 3H-GABA release from the neurons could be detected as early as day 5 in culture. However, during the culture period up to 12 d, the responses to K+, quisqualate, and NMDA were increased. The ontogenetic development of binding sites for quisqualate, kainate, and NMDA in mouse cortex was studied using the radioligands 3H-alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionate (3H-AMPA), 3H-kainate, and 3H-L-glutamate, respectively. The development of binding sites for the different EAA-receptor subtypes showed a good correlation with the development of neuronal 3H-GABA release evoked by the excitatory amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological characterization and differential expression of NMDA receptor subunits in the chicken vestibular system during development

Previous studies demonstrated that in vitro preparations of the isolated vestibular system of diverse animal species still exhibit stable resting electrical activity and mechanically evoked synaptic transmission between hair cells and primary afferent endings. However, there are no reports related to their neurodevelopment. Therefore, this research aimed to examine whether NMDA receptors mediate these electrical signals in an isolated preparation of the chicken vestibular system at three developmental stages, E15, E18, and E21. We found that the spontaneous and mechanically evoked discharges from primary afferents of the posterior semicircular canal were modulated by agonists NMDA and glycine, but not by the agonist d -serine applied near the synapses. Moreover, the individually applied by bath perfusion of three NMDA receptor antagonists (MK-801, ifenprodil, and 2-naphthoic acid) or high Mg²⁺ decreased the resting discharge rate, the NMDA response, and the discharge rate of mechanically evoked activity from these primary afferents. Furthermore, we found that the vestibular ganglion shows a stage-dependent increase in the expression of NMDA receptor subunits GluN1, GluN2 (A-C), and GluN3 (A-B), being greater at E21, except for GluN2D, which was inversely related to the developmental stage. However, in the crista ampullaris, the expression pattern remained constant throughout development. This could suggest the possible existence of presynaptic NMDA receptors. Our results highlight that although the NMDA receptors are functionally active at the early embryonic stages of the vestibular system, NMDA and glycine reach their mature functionality to increase NMDA responses close to hatching (E21).     

Peripheral NMDA and non-NMDA receptors contribute to nociception: an electrophysiological study

The present study investigated the effects of peripheral administration of N-methy-D-aspartate (NMDA) and non-NMDA receptor antagonists on C-fiber evoked responses of the spinal dorsal horn neurons in the spinalized rats. When DL-2-amino-5-phosphonovaleric acid (AP5) (10 mM, 1 mM, 0.1 mM, 20 microl) or 6, 7-dinitroquinoxaline-2, 3-dione (DNQX) (1 mM, 0.1 mM, 0.01 mM, 20 microl) was subcutaneously injected into the receptive field on the hindplantar region, C-fiber evoked responses of the dorsal horn neurons were profoundly inhibited in a dose-dependent manner. Three hours after subcutaneous injection of carrageenan into the ipsilateral hindpaw, NMDA and non-NMDA antagonist-induced inhibition of C-fiber evoked responses was more potent than that in the normal rat (Student's t-test, p < 0.05). In the carragenan-treated rats, DNQX-induced inhibition was stronger than AP-5-induced one (Student's t-test, p < 0.05). The results suggest that peripheral NMDA and non-NMDA receptors are involved in mediating excitation of nociceptors.     

Hippocampal cells primed with quisqualate are depolarized by AP4 and AP6, ligands for a putative glutamate uptake site

The glutamate analog 2-amino-4-phosphonobutyrate (AP4), which in control slices has little effect on Schaffer synaptic responses in hippocampal area CA1, reduces Schaffer responses in slices treated with quisqualate. We have shown that this effect of AP4 is associated with depolarization of CA1 neurons and a persisting small reduction in Schaffer response amplitude. 2-Amino-6-phosphonohexanoate also depressed Schaffer responses following priming with quisqualate, but 2-amino-7-phosphonoheptanoate did not. Treatment with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) or N-methyl-D-aspartate (NMDA) did not sensitize slices to AP4. The pharmacology of this 'priming effect' of quisqualate corresponds to that of a putative uptake site. We suggest the effects of AP4 (and AP6) result from exchange for previously accumulated quisqualate.     

Electrophysiological studies on the role of the NMDA receptor in nociception in the developing rat spinal cord

The present study investigated the effects of spinally applied N-methyl-D-aspartate (NMDA) antagonists 2-amino-5-phosphonovaleric acid (AP5) and ketamine on convergent neurones in the deep dorsal horn of rats, in vivo at different postnatal ages (P) 14, 21, 28, and 56 days. AP5 inhibited the primary afferent fibre input, the C fibre, post-discharge and windup evoked responses in a dose-dependent manner at each age, and was significantly more effective in the pups than adult rats (P<0.03 at 100-microg dose). AP5 100 microg abolished windup almost completely in the pups, whilst the adults required 10-fold higher doses. In contrast there was no difference in ketamine potency between age groups. Windup in the ketamine groups was reduced in a dose-dependent manner equally across all the age groups. The differential inhibitory effects of AP5 and ketamine may be due to postnatal changes in density, localisation and receptor subunit composition, altering receptor affinity and kinetics.     

Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors

A series of ω-phosphono-α-car?ylic acids were tested as antagonists of excitatory amino acid depolarizations and long-term potentiation (LTP) in region CA1 of rat hippocampal slices. The 5- and 7-phosphono compounds (±AP5and±AP7) blocked N-methyl-D-aspartate (NMDA) depolarizations and prevented the induction of LTP of the synaptic field potential and population spike components of the Schaffer collateral response.±AP5and±AP7 did not reduce kainate or quisqualate depolarizations and did not affect unpoten synaptic response amplitude.±AP5, ±AP6and±AP8 did not block amino acid excitant responses or LTP.These results demonstrate that NMDA receptors present in hippocampal region CA1 are not necessary for normal synaptic transmission, but are involved in the initiation of long-term synaptic plasticity.     

Human immunodeficiency virus type 1 Tat protein directly activates neuronal <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">d</Emphasis>-aspartate receptors at an allosteric zinc-sensitive site

The human immunodeficiency virus type 1 (HIV-1) regulatory protein Tat is neurotoxic and may be involved in the neuropathogenesis of HIV-1 dementia, in part via N-methyl-D-aspartate (NMDA) receptor activation. Here, in acutely isolated rat hippocampal neurons, Tat evoked inward currents reversing near 0 mV, with a negative slope conductance region characteristic of NMDA receptor activation. Although the NMDA receptor antagonist ketamine blocked Tat's actions, competitive glutamate- and glycine-binding site antagonists were ineffective (AP-5 and 5,7-dichlorokynurenate, respectively). Evidence for Tat acting at a distinct modulatory site on the NR1 subunit of NMDA receptors was provided by findings that 1 microM Zn(2+) abolished Tat-evoked responses in all neurons tested. Thus, Tat appears to excite neurons via direct activation of the NMDA receptor at an allosteric Zn(2+)-sensitive site.     

Glutamate, without GABA antagonists, induces synchronized discharges in intact hippocampus via NMDA receptors

In rats under urethane anesthesia, iontophoresis of high amounts of glutamate (50-150 nA) in hippocampus caused repetitive field potentials. These synchronized discharges were best recorded in the proximal part of stratum radiatum as positive waves of 10-15 ms duration and of 0.5-5 mV amplitude. A tetrodotoxin-sensitive faster component of 2-5 ms duration was frequently superimposed on the peaks of the positive waves and was followed by a negative wave of 1-6 mV and 20-30 ms. Glutamate-evoked discharges were suppressed by iontophoresis of N-methyl-D-aspartate (NMDA) antagonists, MK-801, Mg2+ and ketamine and also by ketamine injection (i.v. 5-10 mg/kg). The population spikes evoked by fimbrial stimulation were not facilitated by glutamate and the synchronized discharges were suppressed for up to 300 ms following the stimulation, suggesting the presence of an efficient inhibition during glutamate-induced synchronized activity. Glutamate also had no effect on paired-pulse inhibition. No synchronized discharges were recorded with a second electrode separated more than 150 microns from the iontophoretic electrode, suggesting that the activity was local. These data demonstrate that high amounts of glutamate evoke synchronized discharges in hippocampus, possibly through activation of NMDA receptors. The model presented may be utilized to study the mechanisms of synchronization without disinhibition.     

Electrophysiological evidence for the presence of ionotropic and metabotropic excitatory amino acid receptors on dopaminergic neurons of the rat mesencephalon: an in vitro study.

The actions of the ionotropic and metabotropic excitatory amino acid agonists AMPA, quisqualate, kainate, NMDA and trans-ACDP were studied by means of intracellular electrophysiological recordings from dopaminergic neurons of rat mesencephalon in brain slices. It was observed that all these agents evoked an inward current in cells which were voltage-clamped near the resting potential (-50, -60 mV). The membrane responses produced by AMPA, kainate and quisqualate were associated with an increase of the apparent input conductance while the responses induced by NMDA and trans-ACDP were associated with a decrease in the apparent input conductance. Therefore, stimulation of ionotropic and metabotropic amino acid receptors activates inward currents in the dopaminergic cells by different mechanisms.     

Modification of the responses of primate spinothalamic neurons to mechanical stimulation by excitatory amino acids and an N-methyl-D-aspartate antagonist.

Excitatory amino acids (EAAs) are likely to play a key role in sensory transmission in the spinal cord. In the present study, the microiontophoresis technique was used to investigate the effects of L-glutamate (GLUT), N-methyl-D-aspartate (NMDA), and quisqualate (QUIS), as well as an NMDA receptor antagonist, AP-7, on the discharges evoked in nociceptive primate spinothalamic tract (STT) neurons by mechanical stimulation of the skin. Responses to innocuous brushing of the skin were facilitated by GLUT and NMDA (and in some neurons by QUIS) and sometimes reduced by AP-7. GLUT also facilitated the responses to noxious mechanical stimuli. The results are consistent with anatomical evidence for the presence of synapses that contain EAAs on primate STT cells and with the proposal that the co-release of EAAs and neuropeptides may contribute to hyperalgesia.     

Effect of ketamine on spinal cord nociceptive transmission in normal and monoarthritic rats.

The effects of systemically and intrathecally administered ketamine on spinal wind-up of normal and monoarthritic rats were studied by using C-fiber reflex responses evoked by repetitive (0.6 Hz) electric stimulation. Both systemic and intrathecal ketamine induced dose-dependent depression of wind-up activity in normal rats, as revealed by the dose-related inhibitory effects of the drug. At the same intraperitoneal doses, ketamine produced a greater inhibitory effect on wind-up activity of monoarthritic rats, compared to normal animals. The intrathecal administration of ketamine also produced wind-up inhibition, the efficacy being higher in the monoarthritic rats. Results indicate that ketamine depresses spinal wind-up, specially in rats submitted to chronic pain, probably due to its antagonistic properties on dorsal horn NMDA receptors, which play a crucial role in the maintenance of chronic pain.     

Unmyelinated cutaneous afferent neurons activate two types of excitatory amino acid receptor in the spinal cord of Xenopus laevis embryos

The trunk and tail skin of Xenopus laevis embryos near the time of hatching is innervated by the mechanoreceptive free nerve endings of Rohon-Beard neurons, a homogeneous class of cutaneous primary afferent fibers. Rohon-Beard neurons have cell bodies and axons in the dorsal spinal cord, where they monosynaptically excite a population of dorsolaterally situated interneurons (Clarke and Roberts, 1984). EPSPs can be recorded in these dorsolateral interneurons following electrical stimulation of the unmyelinated neurites of Rohon-Beard neurons in the skin. The EPSPs are dual component, consisting of separate fast and slow potentials that are usually evoked synchronously and that closely resemble those described previously in Xenopus and lamprey motoneurons (Dale and Roberts, 1985; Dale and Grillner, 1986). The excitation of dorsolateral interneurons by Rohon-Beard neurons is reduced by the bath application of excitatory amino acid antagonists. Kynurenic acid suppresses both the fast and slow components of the EPSPs, while both (+/-)-2-amino-5-phosphonovaleric acid (APV) and 1 mM magnesium reduce the slow component but have little or no effect on the peak amplitude of the EPSPs. These data suggest that Rohon-Beard neurons release an excitatory amino acid neurotransmitter, which acts simultaneously at both N-methyl-D-aspartate (NMDA) and non-NMDA receptor types. This is the first direct demonstration of dual-component excitatory amino acid-mediated synaptic transmission from cutaneous primary afferent neurons in the vertebrate spinal cord. The bath application of the agonists NMDA, kainate, or quisqualate in salines containing 1 microM TTX depolarized the interneurons and reduced their input resistance, which suggests that the interneurons possess all 3 types of excitatory amino acid receptor. Kynurenic acid strongly inhibits responses to NMDA and kainate, but is relatively less effective against the larger responses of quisqualate in this system.     

Analysis of the effect of quisqualate, N-methyl-D- aspartate and several blockers of amino acid receptors on synaptic transmission in the ampullae of Lorenzini

Effects of bath-application of quisqualate (Q), N-methyl-D-aspartate (NMDA) and antagonists of NMDA-receptors: D-amino-adipate (AA), 2-amino-4-phosphonobutyrate (APB), 2-amino-5-phosphonovalerate (APV) and Mg2+ as well as acidic amino acid antagonist: D-glutamylglycine (DGG) on the synapse between the electroreceptor cells and afferent fibres were studied in the ampullae of Lorenzini. Q (threshold concentration 10(-8) M) and NMDA (threshold concentration 10(-5) M) strongly excited afferent fibres. Neither AA nor APB influenced the resting and evoked activities. APV blocked the synaptic transmission. Mg2+ (30-50 mM) blocked the responses to NMDA, while Q-induced responses were not affected, APV preferentially blocked NMDA-induced responses and in lesser degree--L-aspartate (L-ASP)-induced responses. DGG blocked the synaptic transmission. It is supposed that the synaptic receptor could represent a homogeneous receptor with different binding sites to the known agonists.     

Differential effects of N-methyl-D-aspartic acid and L-homocysteic acid on cerebellar Purkinje neurons

The effects of N-methyl-D-aspartic acid (NMDA) and L-homocysteic acid (LH) were measured on cerebellar Purkinje neurons. In urethane-anesthetized rats, iontophoretic application of NMDA elicited 3 different effects on the spontaneous activity of Purkinje cells: excitation, inhibition and biphasic responses consisting of excitation followed by inhibition. On the other hand, LH elicited excitation, only, regardless of the actions of NMDA on the same neurons. We also examined the effects of various excitatory amino acid antagonists on NMDA- and LH-mediated responses. Excitatory effects of NMDA were antagonized effectively by D.L-2-amino-5-phosphonovalerate (APV), ketamine, gamma-D-glutamylglycine (DGG), D,L-2-amino-7-phosphonoheptanoate (APH), and were not influenced significantly by L-glutamate diethylester (GDEE). Inhibitory responses of NMDA were antagonized by APV, APH and ketamine. LH-mediated excitations were influenced significantly by DGG and ketamine whereas GDEE, APV and APH failed significantly to attenuate the effects of LH. Based on the differential actions of LH and NMDA and the selectivity of NMDA antagonists for NMDA rather than LH-mediated excitations, it appears that the major actions of LH may not be mediated through NMDA receptor sites, at least in the cerebellum.     

Effects of Glutamate Application on the Rhythm of Low Magnesium-induced Epileptiform Activity in Hippocampal Slices of Guinea-pigs

The extracellular concentration of glutamate has previously been reported to increase to more than 10-fold the basal level during seizure activity. In the present study, we tested whether localized increases in extracellular glutamate concentration influence the rhythm of epileptiform discharges in the low-magnesium epilepsy model. In hippocampal slices of guinea-pigs, epileptiform activity was induced by omission of magnesium from the bath fluid. Glutamate and its subreceptor agonists N -methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) were ejected into different strata of the CA3 and CA1 regions using microiontophoretic and micropressure application. Glutamate, NMDA and AMPA applied to the CA3 region, but not to the CA1 region, induced a short-lasting increase in epileptiform discharge frequency, often followed by a transient reduction. The effect was most pronounced with application into the stratum lacunosum-moleculare of the CA3 region and could only be evoked in slices exceeding 400 μm in thickness. The effects on the rhythm of epileptiform discharges induced by NMDA and AMPA were blocked by their specific receptor antagonists. They were not influenced by application of GABA_A and GABA_B receptor antagonists. Changes in somatic membrane potential of CA3 pyramidal neurons did not correlate with changes in the rhythm of epileptiform discharges elicited in this region. The transient suppression of epileptiform discharges that followed the increase in discharge frequency was abolished by an adenosine A₁ receptor antagonist. We propose that localized increases in extracellular glutamate concentration modify the rhythm of epileptiform discharges due to changes in neuronal network activity.     

Depressant actions of γ-d-glutamylaminomethyl sulfonate (GAMS) on amino acid-induced and synaptic excitation in the cat spinal cord

We have investigated the effects of iontophoretically administered gamma-D-glutamylaminomethyl sulfonate (GAMS) on excitation of dorsal horn neurons and Renshaw cells of the cat spinal cord induced by exogenous excitants and by synaptic activation following stimulation of low threshold primary afferent fibers. Comparisons were made between the synaptic depressant effects of GAMS and those of gamma-D-glutamylglycine (gamma DGG) and (+/-)-2-amino-5-phosphonovalerate (APV). At low iontophoretic ejection currents, GAMS showed clear selectivity in antagonizing responses to excitatory amino acids in the order kainate greater than quisqualate greater than L-aspartate greater than NMDA greater than L-glutamate. This selectivity was decreased at high ejection currents, when acetylcholine-induced excitation of Renshaw cells was also reduced. GAMS was equieffective with gamma DGG in depressing both APV-sensitive polysynaptic excitation and APV-resistant monosynaptic excitation of spinal neurons. Ventral root evoked excitation of Renshaw cells was not reduced by GAMS. In some cells a depression of synaptic excitation by GAMS was observed in the absence of an effect on either L-glutamate- or L-aspartate-induced excitation. This raises the possibility that some other endogenous substance may be a transmitter acting at kainate/quisqualate type receptors in the cat spinal cord. However, other factors are discussed which may explain this observation.