Showing papers on "Kainate receptor published in 1983"

Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.

Abstract: 1. The effects of excitatory amino acids and some antagonists applied by ionophoresis to stratum radiatum in the CA1 region of rat hippocampal slices were examined on the locally recorded field e.p.s.p. evoked by stimulation of the Schaffer collateral-commissural projection. 2. L-glutamate, L-aspartate and the more potent and selective excitatory amino acids quisqualate, kainate and N-methyl-DL-aspartate (NMA) depressed the e.p.s.p., presumably through depolarization and/or a change in membrane conductance. 3. The depression induced by kainate considerably outlasted the period of ejection whereas NMA depressions were rapidly reversible and were often followed by a potentiation of the e.p.s.p. In higher doses NMA also depressed the presynaptic fibre volley. The possible involvement of these effects in neurotoxicity and synaptic plasticity is raised. 4. The selective NMA antagonist, DL-2-amino-5-phosphonovalerate (APV) applied in doses which abolished responses to NMA, had no effect on the e.p.s.p. but prevented long term potentiation (l.t.p.) of synaptic transmission evoked by high frequency stimulation of the Schaffer collateral-commissural pathway. Other antagonists which had little or no effect on normal synaptic transmission included D-alpha-aminoadipate (DAA), the optical isomers of 2-amino-4-phosphonobutyrate (APB) and L-glutamate diethylester (GDEE). 5. In contrast, gamma-D-glutamylglycine (DGG), applied in amounts which affected quisqualate and kainate actions as well as those of NMA, was an effective synaptic antagonist whilst having no effect on the presynaptic fibre volley. 6. These results indicate that the synaptic receptor in the Schaffer collateral-commissural pathway may be of the kainate or quisqualate type. Although NMA receptors do not appear to be involved in normal synaptic transmission in this pathway they may play a role in synaptic plasticity. The interaction of L-glutamate and L-aspartate with these receptors is discussed.

The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate

Abstract: 1The interaction of two dissociative anaesthetics, ketamine and phencyclidine, with the responses of spinal neurones to the electrophoretic administration of amino acids and acetylcholine was studied in decerebrate or pentobarbitone-anaesthetized cats and rats. 2Both ketamine and phencyclidine selectively blocked excitation by N-methyl-aspartate (NMA) with little effect on excitation by quisqualate and kainate. 3Ketamine reduced responses to L-aspartate somewhat more than those of l-glutamate; the sensitivity of responses to these two putative transmitters was between that to NMA on one hand and that to quisqualate or kainate on the other. 4On Renshaw cells, ketamine and phencyclidine reduced responses to acetylcholine less than those to NMA but more than those to quisqualate or kainate. Dorsal root-evoked synaptic excitation of Renshaw cells was reduced to a greater extent than that following ventral root excitation. 5Intravenous ketamine, 2.5–20 mg/kg, and phencyclidine, 0.2–0.5 mg/kg, also selectively blocked excitation of neurones by NMA. 6Ketamine showed no consistent or selective effect on inhibition of spinal neurones by electrophoretically administered glycine or γ-aminobutyricacid (GABA). 7The results suggest that reduction of synaptic excitation mediated via NMA receptors contributes to the anaesthetic/analgesic properties of these two dissociative anaesthetics.

The antagonism of amino acid-induced excitations of rat hippocampal CA1 neurones in vitro.

Abstract: 1. The effects of the ionophoretic application of a number of excitatory amino acids and antagonists to the dendrites of CA1 neurones of rat hippocampal slices maintained in vitro were examined. Cells were excited by N-methyl-DL-aspartate (NMA), kainate, quisqualate, L-aspartate and L-glutamate; NMA was unique in causing cells to fire in bursts of repetitive discharges in contrast to the sustained firing seen with the other compounds. 2. D-(-)-alpha-aminoadipate (DAA) and (+/-)-2-amino-5-phosphonovalerate (APV) were selective NMA antagonists, the latter appearing to be the more potent; in addition both compounds potentiated the responses to kainate and quisqualate. L-glutamate excitations were affected less by APV than were those of L-aspartate. The antagonist properties of APV appeared to reside with the D-(-)-isomer. 3. gamma-D-glutamylglycine (DGG) in low ionophoretic doses inhibited NMA-, kainate- and aspartate-induced cell firing but at higher doses the quisqualate and glutamate responses were also decreased. 4. Kainate and NMA responses were blocked by D-(-)-2-amino-4-phosphonobutyrate (D-APB) which also had some action against the excitatory effects of L-aspartate. L-APB had no antagonistic effects, but often produced potentiation of amino acid excitations or was itself an excitant. 5. The effects of NMA and those of kainate and quisqualate were blocked by (+/-)-cis-2,3-piperidine dicarboxylate (PDA), but this compound itself had a direct excitatory effect. L-glutamate diethylester (GDEE) did not show specific antagonism of any amino acid excitations. 6. DGG and APV did not affect ACh excitations and these selective antagonists should be of value in studying the involvement of the excitatory amino acids in synaptic transmission in the hippocampus. Because they are less potent and/or have complicating direct effects PDA, GDEE, D- and L-APB may be less useful in this regard.

Role of excitatory amino acid receptors in mono- and polysynaptic excitation in the cat spinal cord.

Abstract: Three excitatory amino acid antagonists, 2-amino-5-phosphonovalerate (APV), γ-D-glutamyl-glycine (γDGG) and cis-2,3-piperidine dicarboxylate (PDA) have been compared with respect to their ability to block the action of amino acid excitants and both mono- and polysynaptic excitation in the cat spinal cord evoked by stimulation of primary afferent fibres. Each of the three antagonists depressed polysynaptic excitation of dorsal horn neurones. This action correlated with the ability of all of the substances to antagonize responses evoked by N-methyl-D-aspartate (NMDA) and L-aspartate. The order of potency of the antagonists in producing these effects was APV > γDGG = PDA. PDA (particularly) and γDGG also proved to be effective depressants of monosynaptic excitation. This action correlated with the ability of these substances to antagonize quisqualate- and L-glutamate-induced excitation. Antagonism of kainate-induced excitation was usually (but not always) also associated with depression of monosynaptic excitation. These results suggest that, following impulses in low threshold afferent fibres, a transmitter is released from primary afferent terminals which acts at quisqualate- (and possibly kainate-) type receptors and that excitatory interneurones, activated by similar impulses, release a transmitter which acts at NMDA receptors. L-Glutamate and L-aspartate may be the transmitters involved in these monosynaptic and polysynaptic responses, respectively.

Blockade of amino acid‐induced depolarizations and inhibition of excitatory post‐synaptic potentials in rat dentate gyrus.

Abstract: Excitatory post-synaptic potentials (e.p.s.p.s) evoked by stimulation of the medial perforant path and depolarizations induced by excitatory amino acids were recorded from granule cells in the preparation of the hippocampal slice from the rat. The effects of (+/-)-2-amino-5-phosphonovalerate (APV), gamma-D-glutamylglycine (gamma DGG) and cis-2,3-piperidinedicarboxylate (PDA), antagonists of excitatory amino acids on these phenomena were compared. gamma DGG was the most effective antagonist of the e.p.s.p. Its action was reversible and not associated with any change in the passive membrane properties of the granule cells or in the apparent reversal potential of the e.p.s.p. Quantal analysis showed that the reduction in the e.p.s.p. paralleled the decrease in quantal size rather than quantal content, confirming a post-synaptic site of the action of gamma DGG. The potency of gamma DGG against the exogenous agonists was N-methyl-D-aspartate greater than kainate greater than or equal to quisqualate. APV had very little effect on the e.p.s.p. but was a selective antagonist of N-methyl-D-aspartate-induced depolarizations. PDA depolarized granule cells and increased their membrane input resistance. Although gamma DGG was a potent antagonist of both glutamate- and aspartate-induced depolarizations, no clear pattern of specificity could be found. The action of glutamate was unaffected by APV. These results indicate that the receptor for the transmitter at the synapses formed by the fibres of the perforant path with the granule cells is of the quisqualate and/or kainate type. The present data are consistent with the biochemical evidence that glutamate may be the endogenous transmitter at his synapse.

Kainate-Enhanced Release of d-[3H]Aspartate from Cerebral Cortex and Striatum: Reversal by Baclofen and Pentobarbital

Abstract: A study was made of the actions of the excitant neurotoxin, kainic acid, on the uptake and the release of D-[2,3-3H]aspartate (D-ASP) in slices of guinea pig cerebral neocortex and striatum. The slices took up D-ASP, reaching concentrations of the amino acid in the tissue which were 14-23 times that in the medium. Subsequently, electrical stimulation of the slices evoked a Ca2+-dependent release of a portion of the D-ASP. Kainic acid (10(-5)-10(-3) M) produced a dose-dependent inhibition of D-ASP uptake. The electrically evoked release of D-ASP was increased 1.6-2.0 fold by 10(-5) and 10(-4)M kainic acid. The kainate-enlarged release was Ca2+-dependent. Dihydrokainic acid, an analogue of kainic acid with little excitatory or toxic action, did not increase D-ASP release but depressed D-ASP uptake. Attempts were made to block the action of kainic acid with baclofen and pentobarbital, compounds which depress the electrically evoked release of L-glutamate (L-GLU) and L-aspartate (L-ASP). Baclofen (4 X 10(-6)M), an antispastic drug, and pentobarbital (10(-4)M), an anesthetic agent, each inhibited the electrically evoked release of D-ASP and prevented the enhancement of the release above control levels usually produced by 10(-4)M kainic acid. It is proposed that 10(-5) and 10(-4)M kainic acid may enhance the synaptic release of L-GLU and L-ASP from neurons which use these amino acids as transmitters. This action is prevented by baclofen and pentobarbital. In view of the possibility that cell death in Huntington's disease could involve excessive depolarization of striatal and other cells by glutamate, baclofen might be effective in delaying the loss of neurons associated with this condition.

The mechanism of kainic acid neurotoxicity

Abstract: The putative excitatory transmitters glutamate and aspartate, as well as their excitatory analogues, can kill neurones in the central nervous system and may thus be involved in the pathogenesis of various neurodegenerative disorders1. Several studies have suggested that postsynaptic receptors are important in the mechanism of toxicity2. However, presynaptic factors might also be involved because, in some brain areas, the neurotoxicity of kainate (a potent structural analogue of glutamate) is greatly reduced following elimination of afferent excitatory innervation3–6, even though the postsynaptic excitatory potency of kainate may be unaltered in these conditions7. The supply of glutamate from the afferent nerve endings has been suggested to be a necessary factor3,6,8. Recently, Ferkany, Zaczec and Coyle9 concluded from studies on slices of mouse cerebellum that kainate activates presynaptic kainate receptors on parallel fibre terminals to release glutamate and that it is the postsynaptic interaction between kainate and the released amino acid that is instrumental in causing neuronal necrosis. The more direct evidence we report here does not support these conclusions.

Effects of kainic and other amino acids on synaptic excitation in rat hippocampal slices: 1. Extracellular analysis

Abstract: The actions of kainic acid on excitatory synaptic responses in rat hippocampal slices have been investigated and compared with the effects of other excitatory amino acids. Kainate administered iontophoretically or via the superfusate produced a large and long lasting potentiation of the population spike evoked in the CA1 region by Schaffer collateral-commissural stimulation. This potentiation was associated with a reduction in the field EPSP recorded in the dendritic region (stratum radiatum) but with no change in the presynaptic fibre volley or with any long lasting alteration in the antidromic population spike. The results suggest that one effect of kainate may be to produce dendritic depolarisation in CA1 pyramidal neurones. Kainate in equivalent amounts elicited similar potentiations of the population spike recorded in the dentate gyrus in response to either lateral or medial perforant path stimulation. Smaller amounts of kainate than those required to affect either CA1 or dentate pathways were able to potentiate the mossy fibre-evoked population spike in the CA3 region. Folic acid, which shares kainate's ability to produce seizures and distant brain damage when injected into the brain, elicited similar potentiations of synaptic excitation. Higher doses of folate than of kainate were required which is consistent with its weaker epileptogenic actions in vivo. In contrast, N-methyl-aspartate, ibotenate, L-glutamate and L-aspartate were unable to mimic kainate's potentiating action. In higher doses the substances depressed the population spike for long periods. These data suggest that potentiation of synaptic events may underlie the ability of kainate (and folate) to elicit seizures and distant brain damage.

Classification and properties of acidic amino acid receptors in hippocampus. II. Biochemical studies using a sodium efflux assay.

Abstract: The properties of excitatory amino acid receptors in hippocampal slices were analyzed using agonist-induced stimulation of 22Na efflux rate. Several amino acids (L- and D-glutamate, N-methylaspartate) produce progressively smaller responses upon successive applications, whereas D,L-homocysteate does not. Several lines of evidence suggest that depletion of an intracellular pool of 22Na is not responsible for the apparent desensitization. Addition of the amino acids in the presence of an antagonist does not affect the response of the slices to subsequent applications, indicating that desensitization is dependent upon the interaction of the agonist with its receptor. The antagonist D-alpha-aminoadipate discriminates between various excitatory amino acids, completely blocking the responses to N-methylaspartate, D-glutamate, and D,L-homocysteate; partially antagonizing those of quisqualate and kainate; and being without effect on L-glutamate. The order of potency of several excitatory amino acids on the stimulation of 22Na efflux rate in hippocampal slices is highly correlated with their relative effects measured with electrophysiological techniques, but does not correlate with their relative potencies to inhibit [3H]glutamate binding to hippocampal membranes. The similarities in the properties of excitatory amino acid receptors evidenced with the 22Na efflux assay or with the electrophysiological approach in the in vitro hippocampal slice preparation indicate that the same receptors are sampled by the two techniques. The results are discussed in terms of a classification of these receptors into four different groups: a synaptic receptor, activated by D,L-homocysteate (tentatively defined as a G1 receptor), an extrasynaptic glutamate receptor (defined as a G2 receptor), an N-methylaspartate receptor, and a kainate receptor.

In vivo release of [3H]-purines by quinolinic acid and related compounds.

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.

Kainic acid: insights from a neurotoxin into the pathophysiology of Huntington's disease.

Abstract: Kainic acid, a conformationally restricted analog of L-glutamic acid, is a potent neuroexcitant. Consistent with the excitotoxin hypothesis of Olney, intrastriatal injection of kainic acid causes degeneration of neurons with perikarya within the striatum but spares axons passing through or terminating in the region. The striatal kainate lesion shares many neurochemical and histopathologic alterations with those observed in the hereditary neurodegenerative disorder of man, Huntington's Disease. Recent studies on the mechanism of neurotoxicity of kainate indicate that its action is complex and indirect; however, ligand binding studies have revealed specific receptors for kainate. Understanding the fundamental mechanisms involved in excitotoxin action may shed light on the pathophysiology of neurodegenerative disorders such as Huntington's Disease.

Classification and properties of acidic amino acid receptors in hippocampus. III. Supersensitivity during the postnatal period and following denervation.

Abstract: The effects of excitatory amino acids on 22Na efflux rate in rat hippocampal slices were determined at various postnatal days and following removal of a major afferent system. Two weeks after a unilateral hippocampal aspiration, the 22Na efflux induced by potassium ions, D-glutamate, N-methylaspartate, and kainate is significantly decreased in the contralateral intact hippocampus whereas the effect of L-glutamate is substantially increased. Analysis of concentration-response curves suggests that the increased responsiveness to L-glutamate is due to an increase in the maximal effect rather than to changes in the half-maximal concentration for the amino acid. Partial denervation does not detectably change efflux elicited by D,L-homocysteic acid nor does it modify the properties of [3H]glutamate binding to hippocampal membranes. The effects of potassium ions, N-methylaspartate, and kainate but not of D,L-homocysteate are significantly decreased in slices incubated in the absence of calcium. All of the amino acids tested are considerably more potent in slices prepared from 11-day-old rats than in those from adult rats; the differences in responsiveness reflect an increase in maximal effect without changes in the half-maximal concentration. The responses to L-glutamate and D,L-homocysteate decline steadily between postnatal days 11 and 30, at which time adult values are reached. Together, the results from the denervation and development studies suggest a different localization and different modes of regulation for various classes of excitatory amino acid receptors.

Septal deafferentation increases hippocampal adrenergic receptors: correlation with sympathetic axon sprouting.

Abstract: Denervation of the hippocampal formation in adult rats through lesion of the medial septum and diagonal band or by transection of the fimbria/fornix elicits an increase in the number of putative alpha-adrenergic receptor binding sites labeled by the antagonist ligand [3H]WB4101 [2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxane]. This increase in [3H]WB4101 binding is observable at 6 days postlesion, preceding the ingrowth of sympathetic axons into the partially denervated regions of the hippocampus. The receptor up-regulation is specific for lesions of the septal (primarily cholinergic) innervation of the hippocampus. Damage to noradrenergic, dopaminergic, or serotonergic afferents as well as kainate injections in the lateral septum had no effect on [3H]WB4101 binding levels. In vivo muscarinic/cholinergic-receptor blockade does not mimic the effects of the lesion on receptor binding levels or upon axonal sprouting of the sympathetic neurons. Although [3H]WB4101 binding consistently increased after septal deafferentation, there was no clear-cut effect upon the other adrenergic ligands, including [3H]prazosin, [3H]yohimbine, P-[3H]aminoclonidine, or [3H]dihydroalprenolol. These observations can be interpreted as demonstrating a unique and selective adrenergic receptor increase after a nonadrenergic denervation but accompanying the ingrowth of anomalous adrenergic fibers. We suggest several possible relationships between the new binding sites and the ingrowing axons.

Actions of Acidic Amino Acids on the Excitability of Medial Hypothalamic Neurons in the Rat

Abstract: Systemic administration of acidic amino acids produces selective neurotoxic effects on neurons in the arcuate nucleus. However, little is known on the comparative or topographical actions of various a

Alteration by Kainate of Energy Stores and Neuronal-Glial Metabolism of Glutamate In Vitro

Abstract: Kainate was found to decrease the energy charge of cerebellar slices and increase inosine monophosphate levels. In addition, it caused leakage of glutamate and aspartate from the tissue and decreased the synthesis of glutamine from a variety of radioactive precursors. These effects were attributed to alterations in glial cells secondary to massive depolarization of neurons. These results and those of others are discussed in terms of their implication for the mechanism of neurotoxicity of excitatory substances.