Abstract: In vivo release of [3H]-purines from the cortex of anaesthetized rats was measured and the actions of excitatory amino acids and analogues investigated. High KCl, N-methyl-DL-aspartate (NMDLA) and quinolinic acid produced a large increase in basal release of labelled materials. Glutamate, quisqualate and kainate had less effect. The N-methyl-D-aspartic acid (NMDA)-preferring receptor antagonist, 2-amino-7-phosphonohepatanoic acid, significantly reduced the release evoked by NMDLA and quinolinate but not that produced by the other agonists. Kynurenic acid, a compound metabolically related to quinolinic acid, reduced the release due to NMDLA and quinolinate but not glutamate. The results add further support to the suggestion that quinolinic acid acts on the NMDA-preferring receptor.

Abstract: Recent pharmacological and biochemical evidence supports the idea that acidic amino acids act as neurotransmitters at several excitatory synapses in the hippocampus In this paper I review work comparing certain physiological actions of N-methyl-DL-aspartate (NMA) and L-glutamate in a hippocampal slice preparation Intracellular recordings were made from pyramidal neurons bathed in 1 microM tetrodotoxin; agonists were applied by focal ionophoresis NMA evoked calcium spikes and produced an apparent increase in the input resistance of pyramidal cells, whereas glutamate was very weak in these respects The depolarization and conductance change caused by NMA were voltage dependent: both could be abolished by hyperpolarizing the cell to -70 to -90 mV, but no reversal potential could be demonstrated The results of pharmacological and ionic manipulations suggest that the primary action of NMA does not involve reduction of a conventional potassium conductance It is suggested that N-methyl-D-aspartate (NMDA) receptor activation increases a voltage-sensitive calcium conductance leading to a transient rise in cytoplasmic calcium concentration The significance of this event is discussed with respect to the possible synaptic functions of chemically gated, voltage-sensitive calcium channels, and in particular with respect to the possible roles that NMDA receptors might serve in the genesis of long-term potentiation of excitatory synapses in the hippocampus

Abstract: Historically, kainic acid (KA) was selected as a potential exitotoxin because the evidence at the time was consistent with the notion that, as a conformationally restricted analogue of L-glutamate, it was a potent agonist at glutamate receptors (Olney et al., 1974; Coyle and Schwarcz, 1976). Since the first reports of the perikaryal-specific neurotoxic action of intracerebrally injected KA, it has become increasingly apparent that the mechanism of its neurotoxic effects is complex. Consequently, it has been our strategy for clarifying the mechanism of neurotoxicity of KA to focus on receptor specific interactions of the drug. We have felt that this approach might lead to a better understanding of the proximate physiologic events that result in perikaryal-specific neuronal degeneration. Furthermore, the effects of KA might be distinguished from other receptor-specific excitatory amino acid analogues (Watkins and Evans, 1981) such as N-methyl-D-aspartic acid (NMDA) and quisqualic acid as well as more generalized consequences of excessive stimulation of the broad class of the acidic amino acid receptors. These studies have provided evidence of the unique physiologic, pharmacologic and toxicologic properties associated with activation of receptors for KA.

Abstract: Evidence has been obtained for the existence of receptor — receptor interactions between 3H-glutamate and 3H-kainic acid binding sites in rat striatal membranes. Kainic acid (10−6 M) in vitro rapidly reduces the number (11 %) and increases the affinity (12%) in the striatal 3H-glutamate binding sites, while glutamate (10−8 M) in vitro increases the number of striatal 3H-kainic acid binding sites (18 %) and reduces their affinity (46%). The specificity of this interaction is indicated from the fact that N-methyl-D-aspartate (10−6 M) did not modulate the binding characteristics of 3H-glutamate and 3H-kainic acid striatal binding sites. Ibotenic acid (10−6 M) which has a substantial affinity for the 3H-glutamate binding site, mimicked the effects of glutamate on the 3H-kainic acid binding sites. These results may help to explain the important role glutamate seems to play for the neurotoxic action of kainic acid, at least in the striatum where the present experiments indicate that activation of glutamate receptors increases the number of 3H-kainic acid binding sites, so that they may reach a certain critical number required for neurotoxicity. Furthermore, kainic acid by increasing the affinity of the 3H-glutamate binding sites may set the excitatory glutamate synapses into operation at lower concentrations of glutamate, in this way increasing the vulnerability of the striatal nerve cells to kainic acid neurotoxicity. The small percent changes in the 3H-glutamate and 3H-kainic acid binding sites are probably amplified considerably as the signal pass via the membrane to its final biological effector.

Abstract: “Excitotoxins” represent a very special group of neurotoxic substances, in that they act upon specific somatic and dendritic receptors such that if the excitation produced is of sufficient magnitude, the neurones die.

Abstract: A brain peptide with high affinity (420 nM) and marked specificity for brain receptor sites labeled with L-[3H]glutamate has been identified. Amino acid analysis and mass spectroscopy indicate that the peptide is N-acetylaspartylglutamate. The peptide exhibits potent convulsant properties when injected into the rat hippocampus, similar to those produced by the glutamate receptor agonist, quisqualic acid. These findings raise the question whether endogenous brain peptides enriched in acidic amino acids may serve as excitatory neurotransmitters.

Abstract: A physiological and pharmacological investigation of a novel endogenous excitant, quinolinic acid, was carried out in male rats using conventional iontophoretic techniques. It was established that quinolinic acid responses were preferentially reduced by antagonists acting at the N-methyl-D-aspartate (NMDA) preferring receptor, such as (+/-)-2-amino-7-phosphono-heptanoic acid and 1-hydroxy-3-amino-pyrrolidone-2. Glutamic acid diethyl ester reduced responses to quinolinic acid, quisqualic acid and NMDA with no clear specificity. Streptomycin, thought to act at the quisqualic acid receptor, largely spared quinolinic acid responses, being more effective against quisqualic acid evoked excitations. It is therefore suggested that quinolinic acid acts primarily at the NMDA receptor. In addition, the sensitivity of various components of the neuraxis to quinolinic acid was assessed and compared with glutamate and NMDA. Neurons in the spinal cord and cerebellum were largely unresponsive to quinolinate, whereas cells in the neocortex, striatum and hippocampus responded to this agonist to a similar degree as glutamate. In the cortex quinolinate was about one-fifth as active as NMDA, which together with quinolinic acid was much less active in the spinal cord and cerebellum. It is concluded that the possibility that quinolinic acid has a neurotransmitter type function at central "amino acid" receptors merits further investigation.

Abstract: Glutamate is thought to serve as a major excitatory neurotrans-mitter throughout the central nervous system (CNS)1,2; electrophysiological studies indicate that its action is mediated by multiple receptors. Four receptors have been characterized by their selective sensitivity to N-methyl-D-aspartate (NMDA), kainic acid (KA), quisqualic acid (QA) and 2-amino-4-phosphonobutyric acid (APB)1,3–5. Electrophysiological evidence indicates that these receptors are all present in the rat hippocampus and that the anatomically discrete synaptic fields within the hippocampus exhibit differential sensitivity to the selective excitatory amino acid agents3,6,7. Thus, we have used the hippocampus as a model system to investigate possible subpopulations of 3H-L-glutamate binding sites. By using quantitative autoradiography, the pharmacological specificity of 3H-L-glutamate binding in discrete terminal fields was determined. We report here that there are at least four distinct classes of 3H-L-glutamate binding sites which differ in their anatomical distribution, pharmacological profile and regulation by ions. Two of these sites seem to correspond to the KA and NMDA receptor classes, and a third site may represent the QA receptor. The fourth binding site does not conform to present receptor classifications. None of these binding sites corresponds to the major glutamate binding site observed in biochemical studies8–12.