The distribution of some nitrogenous constituents in the tea plant.
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Amides↗
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Electrophysiological evidence for the existence of NMDA and non-NMDA receptors on rat ventral tegmental dopamine neurons.
In vitro extracellular single-unit recordings from rat midbrain slices were used to assess the effects of excitatory amino acid agonists on the activity of A10 dopamine neurons. N-methyl-D-aspartic acid (NMDA), kainic acid (KA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) elicited dose-dependent increases in firing rates. The relative potencies for the 3 compounds was AMPA > KA > NMDA. None of the excitations was accompanied by burst firing, but frequently periods of nonrecordable activity occurred following pronounced stimulation. Concurrent application of the excitatory amino acid antagonist CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylate) selectively blocked the excitations elicited by NMDA but not by KA or AMPA. Likewise the selective non-NMDA antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline] blocked only the excitatory effects of AMPA and KA but not those elicited by NMDA. NBQX appeared to be less potent at antagonizing KA than AMPA. These results suggest that mesolimbic-mesocortical dopamine neurons possess both NMDA and non-NMDA receptors, and possibly distinct AMPA and KA recognition sites.
Amino Acids↗
Reversion of L-lysine inhibition of penicillin G biosynthesis by 6-oxopiperidine-2-carboxylic acid in Penicillium chrysogenum PQ-96.
6-Oxopiperidine-2-carboxylic acid (OCA; cyclic alpha-aminoadipic acid) reverses the L-lysine inhibition of penicillin G production by Penicillium chrysogenum PQ-96. The reaction probably depends on the recovery of L-alpha-aminoadipic acid for penicillin G production from OCA.
2-Aminoadipic Acid↗
Depolarization elicits, while hyperpolarization blocks uptake of endogenous glutamate by retinal horizontal cells of the turtle.
We have employed an immunoreaction against glutamate to qualitatively demonstrate varying levels of glutamate in retinal horizontal cells of the turtle. Glutamate-like immunoreactivity (GLI) in horizontal cells could be demonstrated after glutamate decarboxylase was inhibited by aminooxyacetic acid (AOAA) and its degradation to GABA was blocked. Depolarization of horizontal cells by kainic acid (KA) induces strong glutamate immunoreactivity in these cells, whereas hyperpolarization by 2,3-cis piperidine dicarboxylate (PDA) abolishes glutamate-like immunoreactivity in horizontal cells. When glutamate release from cones and bipolar cells is blocked in the absence of calcium, or when glutamate uptake is blocked by DL-threo beta-hydroxy aspartate, KA/AOAA treatment of the retina does not induce GLI in horizontal cells. Our data show that horizontal cells are capable of taking up glutamate from the endogenous retinal pool in an activity dependent way. Our interpretation of these findings is that retinal horizontal cells are capable of regulating glutamate levels in the extracellular space of the cone pedicle complex by an activity-dependent uptake system. We suggest that inhibition of glutamate uptake upon hyperpolarization rather than inhibition of GABA release may evoke the antagonistic surround response of retinal bipolar cells.
Aminooxyacetic Acid↗
Reticulospinal neurones activate excitatory amino acid receptors.
Paired intracellular recordings were used to study the monosynaptic excitatory postsynaptic potentials (EPSP) in lamprey motoneurones evoked by stimulation of single reticulospinal Müller and Mauthner cells. The chemical component of the synaptic potentials was depressed by both application of the non-selective excitatory amino acid antagonists kynurenic acid and cis-2,3-piperidine dicarboxylate. The N-methyl-D-aspartate (NMDA) antagonists Mg2+ and 2-amino-5-phosphonovalerate caused a selective depression of a late component of the EPSP. Thus, fast-conducting reticulospinal neurones appear to release an excitatory amino acid acting at both NMDA and non-NMDA receptors.
2-Amino-5-phosphonovalerate↗
Cortically evoked excitatory synaptic transmission in the cat red nucleus is antagonised by D-AP5 but not by D-AP7.
Extracellular recordings were made from magnocellular red nucleus neurons (mRN) in alpha-chloralose (50 mg/kg, iv.) anaesthetised cats. Iontophoretically applied N-methyl-D-aspartate (NMDA) excited the neuronal firing which was antagonised by 4 selective NMDA receptor antagonists: 2-amino-5-phosphonopentanoate (AP5), 2-amino-7-phosphonoheptanoate (AP7), RS-4-(phosphonomethyl) piperazine-2-carboxylic acid (PMPC) and R-4-(3-phosphonopropyl) piperazine-2-carboxylic acid (CPP), whereas AMPA responses were uneffected. Monosynaptic excitatory responses were produced by stimulation of the sensorimotor cortex. These responses were reduced and often abolished by AP5 and PMPC but not by AP7 or CPP. It is postulated that two NMDA receptor subtypes exist on mRN neurones.
2-Amino-5-phosphonovalerate↗
Effects of N-methyl-D-aspartate receptor antagonists on cisplatin-induced emesis in the ferret.
Glutamate may be a key transmitter in the emetic reflex arc. The present investigation focussed on the involvement of the NMDA subtype of glutamate receptors in cisplatin-induced emesis. Ferrets were injected with cisplatin (10 mg/kg i.v.) and either of the non-competitive NMDA receptor antagonists dextromethorphan or memantine, or the competitive receptor antagonist CGS 19755. In order to determine whether there is a synergism between NMDA blockers and 5-HT3 receptor antagonists, a submaximal dose of granisetron (0.05 mg/kg) was given alone or in combination with either dextromethorphan or memantine. The latency for the onset of emesis as well as the total number of vomits and retches over 3 hr were determined. In controls, the latency for emesis was 73 +/- 6 min and the total number of vomits and retches 143 +/- 17. The corresponding figures for animals treated with dextromethorphan, 10 and 20 mg/kg, were 89 +/- 19 min (p > 0.05) and 50 +/- 17 (p = 0.008), and 113 +/- 18 min (p > 0.05) and 22 +/- 9 (p = 0.004), respectively. At 10 mg/kg, dextromethorphan failed to enhance the antiemetic effect of granisetron which by itself provided 90% inhibition. While memantine (2.5 or 5.0 mg/kg) did not have an effect per se, it tended to reduce the antiemetic effect of granisetron. CGS 19755 (10 mg/kg) provided a partial protection against cisplatin-induced emesis (latency: 111 +/- 23, number of vomits and retches 30 +/- 11). None of the NMDA receptor antagonists was free of behavioural effects (e.g. some sedation) at antiemetic doses. It is concluded that NMDA receptor antagonists may afford protection against cisplatin-induced emesis but the specificity of this effect is uncertain since it may relate to general CNS depression.
Animals↗
NMDA receptor activity in learning spatial procedural strategies II. The influence of cerebellar lesions.
Experimental data support the involvement of cerebellar circuits in the acquisition of spatial procedural competences. Since the ability to acquire new procedural competences is lost when cerebellar regions are lesioned or when NMDA receptor activity is blocked, we analyzed whether the learning of explorative strategies is affected by blocking NMDA receptor activity in the presence of cerebellar lesions. To this aim, the NMDA receptor antagonist (CGS 19755, 7 mg/kg) was administered i.p. to un-lesioned rats, or rats subjected to total ablation of the cerebellum or to hemi-cerebellectomy. CGS 19755 and cerebellectomy both produced water maze behavior characterized by circling. Administration of CGS 19755 did not modify the Morris Water Maze (MWM) peripheral circling behavior of cerebellectomized animals. Circling was the dominant strategy of hemicerebellectomized animals in the absence of drugs. However, increasingly compulsive circling was observed under the action of CGS 19755. Circling was not observed if the drug-treated animals (un-lesioned or lesioned) had been previously trained. In conclusion, the NMDA antagonist caused severe impairment in the acquisition of spatial procedures, thus mimicking the consequences of cerebellar ablation on spatial procedural learning. Based on the present findings, we hypothesize that cerebellar NMDA receptor activity is involved in the acquisition of procedural spatial competence.
Analysis of Variance↗
Neuroprotective interaction effects of NMDA and AMPA receptor antagonists in an in vitro model of cerebral ischemia.
An in vitro model of ischemia was developed and characterized using the acute rat hippocampal slice preparation. Neuroprotective concentrations of several competitive and noncompetitive glutamate subtype-selective antagonists (CGS-19755, MK-801, YM90K and GYKI-52466) were initially determined in anoxia-enhanced agonist-induced excitotoxicity experiments. Concentrations which proved to be effective in these studies were subsequently tested for their effectiveness against an ischemic episode. Ischemia was defined as a 30-min exposure to aglycemic media ending in 5 min of concurrent anoxia, a protocol which was arrived at by empirically determining the effect of various hypoglycemic and anoxic insults on the ability of hippocampal slices to retain their electrophysiological viability. Exposure to such an ischemic episode resulted in a loss of viability by most slices, an effect which was strongly dependent on extracellular calcium. AMPA antagonists applied alone produced no neuroprotective effect in the present model of in vitro ischemia, while NMDA antagonists applied alone had a modest neuroprotective effect. In contrast, the coapplication of 10 microM MK-801 and 300 microM GYKI-52466, noncompetitive NMDA and AMPA receptor antagonists, respectively, resulted in almost complete neuroprotection. This protection was comparable to that obtained by withholding extracellular calcium, indicating that the toxic effects of glutamate receptor overstimulation can be accounted for solely by calcium influx. The effect of this combination treatment on the survival rate of hippocampal slices was synergistic, that is greater than the sum of the effects of the individual compounds. The results indicate that neuroprotection against acute ischemic insults may require a combination therapy approach.
Animals↗
CP-101,606, a potent neuroprotectant selective for forebrain neurons.
The neuroprotective activity of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606), an N-methyl-D-aspartate (NMDA) receptor antagonist structurally similar to ((+/-)-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-++ +piperidineethanol (ifenprodil), was investigated in neurons in primary culture. CP-101,606 potently and efficaciously protected hippocampal neurons from glutamate toxicity but was > 900-fold less effective for cerebellar granule neurons. The neuroprotective activity in the hippocampal neurons is mediated through a high affinity binding site distinct from the agonist and thienylcyclohexylpiperidine (TCP) binding sites of the NMDA receptor. Autoradiography indicates the CP-101,606 binding site is localized in forebrain, most notably in hippocampus and the outer layers of cortex. The functional selectivity for hippocampal neurons, forebrain localization of binding sites, and structural relation to ifenprodil suggest that CP-101,606 is an NMDA antagonist highly selective for NR2B subunit containing receptors.
Animals↗
Regional distribution and pharmacological characteristics of [3H]N-acetyl-aspartyl-glutamate (NAAG) binding sites in rat brain.
Autoradiographical studies revealed that 10 nM [3H]N-acetyl-aspartyl-glutamate (NAAG) labelled grey matter structures, particularly in the hippocamus, cerebral neocortex, striatum, septal nuclei and the cerebellar cortex. The binding was inhibited by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine (DCG IV), an agonist at group II metabotropic glutamate receptors (mGluR II). (RS)-alpha-Methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-cyclopropyl-4-phosphonoglycine (CPPG) and (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE), all antagonists at mGluR II and mGluR III, also inhibited [3H]NAAG binding. Other inhibitors were (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD), a broad-spectrum mGluR agonist with preference for groups I and II and the mGluR I agonists/mGluR II antagonists (S)-3-carboxy-4-hydroxyphenylglycine (3,4-CHPG) and (S)-4-carboxy-3-hydroxyphenylglycine (4,3-CHPG). Neither the mGluR I specific agonist (S)-dihydroxyphenylglycine nor any of the ionotropic glutamate receptor ligands such as kainate, AMPA and MK-801 had strong effects (except for the competitive NMDA antagonist CGS 19755, which produced 20-40% inhibition at 100 microM) suggesting that, at low nM concentrations, [3H]NAAG binds predominantly to metabotropic glutamate receptors, particularly those of the mGluR II type. Several studies have indicated that NAAG can interact with mGluR II and the present study supports this notion by demonstrating that sites capable of binding NAAG at low concentrations and displaying pharmacological characteristics of mGluR II exist in the central nervous tissue. Furthermore, the results show that autoradiography of [3H]NAAG binding can be used to quantify the distribution of such sites in distinct brain regions and study their pharmacology at the same time.
Alanine↗
Effects of N-methyl-D-aspartate antagonists on different measures of motion sickness in cats.
Because N-methyl-D-aspartate (NMDA) antagonists prevent cisplatin-induced emesis and NMDA receptors are in both emetic pathways and structures associated with the final common pathway for vomiting, they have the potential to be broad-spectrum antiemetics. This was evaluated by determining their effects on motion sickness in cats. The measures included the number vomiting, the number of symptom points, which reflect activity early in the final common path and the duration of the retch/vomit sequence, which reflects activity late in the path. Dextrorphan, ketamine and dextromethorphan decreased the number vomiting with the same rank order of potency as at NMDA receptors. Additional studies with 1,3-dio-tolylguaninidine (DTG) and haloperidol ruled out a role for sigma receptors. The NMDA antagonists produced a nonsignificant dose-dependent decrease in symptoms and had no effects on the duration of vomiting. They also produced motor abnormalities at the highest doses. The competitive antagonist LY 233053 also decreased the number vomiting without altering the duration. It produced a nonsignificant non-dose-dependent decrease in symptoms and had no effects on gross motor output. The results are consistent with a broad spectrum of antiemetic efficacy with at least a part of its action in the early to middle portions of the final common pathway for vomiting. Additional actions on the vestibular nuclei are possible.
Analysis of Variance↗
Effects of CNQX, APB, PDA, and kynurenate on horizontal cells of the tiger salamander retina.
Effects of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 2-amino-4-phosphonobutyrate (APB), cis-2,3-piperidine dicarboxylic acid (PDA), and kynurenate (KYN) on the depolarizing actions of glutamate and kainate on horizontal cells (HCs) were studied in the larval tiger salamander retina. APB, PDA, and KYN hyperpolarized the HCs, but they failed to block either the actions of glutamate and kainate, or the HC light responses. APB and PDA did not cause membrane polarizations in either rods or cones, suggesting that the HC hyperpolarizations were not mediated by presynaptic actions of these compounds. CNQX, the newly synthesized non-NMDA (N-Methyl-D-Aspartate) receptor antagonist, blocked the HC light responses and the action of kainate, but not that of glutamate. These results suggest that the synaptic receptors in the tiger salamander HCs are probably non-NMDA although extra-synaptic NMDA receptors may exist in these cells.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Structure-activity studies of 6-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonists. 2. Effects of distal acid bioisosteric substitution, absolute stereochemical preferences, and in vivo activity.
We have explored the excitatory amino acid antagonist activity in a series of decahydroiso-quinoline-3-carboxyic acids, and within this series found the potent and selective AMPA antagonist (3SR,4aRS,6RS,8aRS)-6-(2-(1H-tetrazol-5-yl )ethyl) decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we looked at the structure-activity relationships for AMPA antagonist activity in this series of compounds. We have already shown that 1 had the optimal stereochemical array and that AMPA antagonist activity was maximized for a two-carbon spacer separating a tetrazole from the bicyclic nucleus. In this paper, we explored the effects of varying the distal acid and the absolute stereochemical preferences of many of these analogs. We looked at a variety of different acid bioisosteres, including 5-membered hetereocyclic acids such as tetrazole, 1,2,4-triazole, and 3-isoxazolone; carboxylic,phosphonic, and sulfonic acid; and acyl sulfonamides. Compounds were evaluated in rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([3H]AMPA), NMDA ([3H]CGS 19755), and kainic acid ([3H]kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 microM), NMDA (40 microM), and kainic acid (10 microM). A number of compounds from this and the preceding paper were also evaluated in mice for their ability to block maximal electroshock-induced convulsions and ATPA-induced rigidity in mice.
Animals↗
Bipolar cells in the mudpuppy retina use an excitatory amino acid neurotransmitter.
The bipolar cells of the vertebrate retina are the principal neuronal elements which transmit photoreceptor activity from the outer to the inner retina. An important function of the bipolars is to segregate photoreceptor input into independent ON and OFF channels which are subserved, respectively, by the depolarizing and hyperpolarizing bipolar subtypes. Ultrastructural and physiological observations suggest that chemical neurotransmission is the predominant means of bipolar input to the inner retina. Both ON and OFF bipolars apparently release excitatory transmitters. Histological studies with cytotoxic agents and physiological studies indicate that third-order neurones have excitatory amino acid receptors. In ON-OFF amacrine and ganglion cells, which receive input from both bipolars, ON and OFF excitation have a similar ionic basis, suggesting that the same transmitter may be released by both types of bipolars. We have now found that (+/-)cis-2,3-piperidine dicarboxylic acid (PDA), a new excitatory amino acid antagonist, blocks bipolar input to the inner retina and thus suggests that an excitatory amino acid is a bipolar cell transmitter.
Amino Acids↗
Modification of the Xenopus electroretinogram by actions of glycine in the proximal retina.
The electroretinogram (ERG) was recorded from the Xenopus retina, to examine the effects of glycine and strychnine on these responses and to determine the origins of these changes. Glycine at concentrations between 0.1 and 10 mM reduced the b- and d-waves of the ERG in a dose-dependent manner, while strychnine increased their amplitude. 2-Amino-4-phosphonobutyric acid (APB) reduced the b-wave and blocked the effect of glycine, but not strychnine, on the d-wave. When the d-wave had first been blocked by kynurenic acid (KYN) or reduced by (+/-)cis-2,3-piperidine dicarboxylic acid (PDA) the b-wave was enhanced by glycine, but not by strychnine. N-methyl-DL-aspartate (NMDLA), which alters responses in the proximal retina only, blocked the effects of glycine and strychnine on the ERG. This suggests that the glycinergic effects on the ERG are at least partly mediated by processes in the proximal retina. The results further support the suggestion that inhibitory neurotransmitters in the proximal retina may modulate both the b- and d-waves of the Xenopus ERG.
Aminobutyrates↗
Changes in eye growth produced by drugs which affect retinal ON or OFF responses to light.
The interaction between drugs which affect ON and OFF responses to light and ocular growth was investigated in 154 eyes of newly-hatched chicks raised with normal vision or monocular occlusion with regular intravitreal injections of APB (2-amino-4 phosphonobutyric acid) or PDA (cis 2,3-piperidine-dicarboxylic acid). The experimental results indicate that APB, at a dose sufficient to abolish the b-wave of the electroretinogram (but not to show extensive damage to the retinal neurons at the light microscopic level), caused a significant decrease in the axial growth of the eyes when compared with normal eyes. APB did not result in a significant difference in the growth rates of the occluded eyes compared with occluded controls. By contrast, injection of PDA into occluded eyes at a dose which reduced the response at light offset in the electroretinogram (and also affected the ON-response), caused a dramatic reduction in elongation of those eyes compared with occluded controls. Injection of PDA into eyes raised in a normal visual environment did not induce a significant difference from the growth rate of normally reared control eyes. These growth changes support the hypothesis that drugs which affect the physiological function of the retina, in particular, the strength of the ON and OFF responses, interact with the visual rearing environment to cause a consistent pattern of changes to eye growth and refractive error.
Aminobutyrates↗
Antagonism of excitatory amino acid-induced and synaptic excitation of spinal neurones by cis-2,3-piperidine dicarboxylate.
In tests on neurones in the cat spinal cord in vivo, and frog and immature rat spinal cord in vitro, cis-2,3-piperidine dicarboxylate (cis-2,3-PDA) produced the following effects: (1) selective antagonism of amino acid-induced responses, compared with responses to other putative transmitters; (2) effective antagonism of kainate and quisqualate-induced responses in addition to responses induced by N-methyl-D-aspartate (NMDA) and other excitatory amino acids; (3) partial NMDA-like agonist action; (4) antagonism of dorsal root-evoked excitation of Renshaw cells; (5) potentiation of acetylcholine- and ventral root-evoked excitation of Renshaw cells. This unique spectrum of action may be useful for transmitter receptor characterization in the vertebrate central nervous system.
Alanine↗