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PubMed1985

Effect of excitatory amino acids and analogues on [3H]acetylcholine release from amacrine cells of the rabbit retina.

The pharmacology of cholinergic amacrine cells has been further studied by examining the effects of excitatory amino acids and antagonists on [3H]acetylcholine (ACh) release from the retinas of anaesthetized rabbits. Exposure of the retina to glutamate (5 mM), aspartate (5 mM), kainate (8 microM) and quisqualate (8 microM) abolished the light-evoked release of [3H]ACh but increased the spontaneous resting release four- to fivefold. N-methyl-D-aspartate (NMDA) (5 mM) in normal Krebs bicarbonate medium abolished the light-evoked release of [3H]ACh but did not affect the resting release. However, in Mg-free medium, NMDA (0.5 mM) abolished the light-evoked release of [3H]ACh and increased the resting release fivefold. The effects of other agonists were not altered in Mg-free medium. The amplitude of the electroretinogram (e.r.g.) b-wave was not significantly reduced by glutamate, aspartate or NMDA (in normal or Mg-free medium). Kainate and quisqualate reduced the b-wave amplitude to approximately 50 and 30% of controls respectively. The general excitatory amino acid antagonist, cis-2,3-piperidine dicarboxylic acid (PDA) (2 mM) blocked the light-evoked release of [3H]ACh, but had no significant effect on the e.r.g. b-wave amplitude or on the resting release of [3H]ACh. L(+)-2-amino-4-phosphonobutyrate (L(+)-APB) decreased the light-evoked release of [3H]ACh and the amplitude of the e.r.g. b-wave in parallel (correlation coefficient 0.995). D(-)-APB had similar effects but was fifteen times less potent. Since the L(+)-compound is known to mimic the photoreceptor transmitter on the depolarizing, but not hyperpolarizing, bipolar cells, these results strongly suggest that the [3H]ACh released in response to light originates mainly from the 'on' (displaced) cholinergic amacrine cells. Our experiments give no information on the origin of the spontaneously released [3H]ACh. PDA (2-5 mM) blocked the effects of glutamate, aspartate, kainate, quisqualate and NMDA on the resting release of [3H]ACh. In contrast, D(-)-APB (5 mM), which is a relatively non-specific excitatory amino acid antagonist in the spinal cord, blocked only the actions of kainate and had no blocking effect on the actions of glutamate or aspartate (the putative bipolar cell transmitters) or NMDA. D(-)-2-amino-5-phosphonovalerate (APV) which is a relatively selective NMDA antagonist in the spinal cord failed to discriminate between the effects of kainate and NMDA on the resting release of [3H]ACh. D-alpha-aminoadipate at concentrations up to 5 mM had no effect on any of the agonists.(ABSTRACT TRUNCATED AT 400 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed2004

Acute nociceptive somatic stimulus sensitizes neurones in the spinal cord to colonic distension in the rat.

The common co-existence of fibromyalgia and chronic abdominal pain could be due to sensitization of spinal neurones (SNs), as a result of viscero-somatic convergence. The objective of this study is to explore the influence of acute nociceptive somatic stimulation in the form of acid injections, into the ipsilateral somatic receptive field of neurones responsive to colorectal distension (CRD), and the potential role of ionotropic glutamate receptors on sensitization. Action potentials of CRD-sensitive SNs were recorded extracellularly from the lumbar (L(2)-L(5)) spinal cord. Stimulus-response functions (SRFs) to graded CRD (10-80 mmHg, 30 s) were constructed before and 30 min after ipsilateral injection of low pH (4.0, 100 microl) saline into the somatic receptive fields. In some experiments, cervical (C(1)-C(2)) spinalization was performed to eliminate supraspinal influence. The selective NMDA receptor antagonist CGS 19755 and AMPA receptor antagonist NBQX were injected (25 micromol kg(-1), i.v.) to examine their influence on sensitization. Three types of neurones were characterized as short-latency abrupt (SLA, n = 24), short latency sustained (SLS, n = 12), and long-latency (LL, n = 6) to CRD. Ipsilateral injection of low pH (4.0) in the somatic receptive field, but not the contralateral gastrocnemius (GN) or front leg muscles, sensitized responses of these neurones to CRD. Spinalization had no influence on the development of low pH-induced sensitization. Both CGS 19755 and NBQX significantly attenuated the sensitized response to CRD in intact and spinalized animals. Acute nociceptive somatic stimulus sensitizes CRD-sensitive SNs receiving viscero-somatic convergence. The sensitization occurs at the spinal level and is independent of supraspinal influence. Ionotropic glutamate receptors in the spinal cord are involved in sensitization.

Acids↗
PubMed1992

Gamma-aminobutyric acid-glutamate interaction in the control of somatostatin release from hypothalamic neurons in primary culture: in vivo corroboration.

Recent studies have provided new data on the neuroendocrine role of glutamate (the major excitatory neurotransmitter) on somatostatin release. The neuroendocrine role of gamma-aminobutyric acid (GABA) (the major inhibitory neurotransmitter) on this same secretion, is also well established. Our objective was thus to investigate whether GABA and glutamate, which have opposite neurotransmission signals, could interact in the control of hypothalamic somatostatin release. Pharmacological manipulations of the two types of receptors were performed in vitro on primary cultures of hypothalamic neurons secreting somatostatin. We found that tonic release of somatostatin was reduced by 76% in the presence of tetrodotoxin (TTX) and was regulated by endogenous secretion of glutamate and GABA. CGS 19755, a highly selective N-methyl-D-aspartate (NMDA) receptor antagonist, significantly reduced tonic somatostatin secretion whereas it was strongly increased by picrotoxin and bicuculline, two GABAA antagonists. When CGS 19755 was applied with picrotoxin, somatostatin release was the same as levels obtained in the control group with TTX. GABA reduced tonic somatostatin release (in the presence or absence of TTX), and glutamate-stimulated secretion in a dose-dependent manner. Picrotoxin stimulation of tonic somatostatin release was additive with that obtained after glutamate stimulation and was also dose-dependent. This interaction was also studied in vivo in unanesthetized rats bearing a push-pull cannula stereotaxically implanted into the median eminence. Ip injected CGS 19755 (an antagonist that can freely permeate the blood-brain barrier) completely blocked the peak secretion of somatostatin observed after ip picrotoxin administration, whereas there was no significant effect when it was injected alone. These findings corroborated our in vitro data and allow us to postulate that GABA and glutamate interact in the control of somatostatin.

Animals↗
PubMed1995

Inhibitory effect of clopidogrel, vapiprost and argatroban on the middle cerebral artery thrombosis in the rat.

This study investigated the roles of thromboxane A2 (TXA2), ADP and thrombin in middle cerebral artery (MCA) thrombosis in the rat. The rat MCA was occluded by a thrombus induced by the photochemical reaction of rose bengal by green light that causes endothelial damage followed by platelet adhesion, aggregation and formation of a platelet and fibrin-rich thrombus at the site of the photochemical reaction. Vapiprost, a specific TXA2-receptor antagonist; clopidogrel, which has the thienopyridine structure of ticlopidine and is a more potent inhibitor of ADP-induced platelet aggregation than ticlopidine; argatroban, a specific thrombin inhibitor; or heparin was administered intravenously before rose bengal injection. The MCA local blood flow was monitored by a laser Doppler flowmeter. The MCA was occluded by thrombus about 5 min after the initiation of the photochemical reaction. Vapiprost, clopidogrel and argatroban all significantly prolonged the time taken for the thrombotic occlusion of the MCA, but in this respect, heparin was ineffective. Our observations suggest that vapiprost and clopidogrel are useful antithrombotic agents against platelet and fibrin-rich thrombi. The effect of argatroban is attributable to inhibition of thrombin-induced platelet activation and fibrin generation. The thrombosis model described in this study is useful for understanding the mechanism(s) of thrombogenesis in the rat MCA and may be applied to other mammalian species.

Animals↗
PubMed2000

Systemic nicotine stimulates dopamine release in nucleus accumbens: re-evaluation of the role of N-methyl-D-aspartate receptors in the ventral tegmental area.

Systemic nicotine stimulates dopamine (DA) release in the nucleus accumbens (NAcc), and N-methyl-D-aspartate (NMDA) receptors in the ventral tegmental area (VTA) appear to be involved. However, it is not known whether the secretion of DA elicited by nicotine depends on the tonic and/or phasic activation of NMDA receptors by glutamate (Glu). To clarify this, in vivo microdialysis was conducted in freely moving, alert rats to measure DA and Glu overflows in the NAcc and Glu in the VTA. Nicotine (0.065, 0.09, or 0.135 mg/kg delivered i.v. at 0.09 mg/kg/60 s via a jugular cannula) dose dependently stimulated NAcc DA secretion (P <.05). However, 0.065 mg/kg nicotine failed to stimulate Glu release in the VTA, whereas higher doses of nicotine (> or =0.09 mg/kg) were effective (P <.05). Administering the competitive NMDA receptor antagonists, 2-amino-5-phosphonopentanoic acid (AP-5; 1 mM) or 0.2 mM cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) through the VTA probe, abolished NAcc DA release after 0.065 mg/kg nicotine (P <.01) and reduced the response to 0.09 mg/kg nicotine. Therefore, the NAcc DA response to a relatively low dose of nicotine depends on the tonic activation of NMDA receptors in the VTA. In contrast, infusing 1 mM 2-amino-5-phosphonopentanoic acid or 1 mM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, into the NAcc through the microdialysis probe had no effect on NAcc DA secretion in response to 0.09 mg/kg nicotine. These findings, coupled with data showing that Glu secretion in the VTA was stimulated only by higher doses of nicotine, indicate that the phasic release of VTA Glu is involved in the NAcc DA response to higher doses of nicotine (> or =0.09 mg/kg).

2-Amino-5-phosphonovalerate↗
PubMed2001

Primate photopic sine-wave flicker ERG: vector modeling analysis of component origins using glutamate analogs.

PURPOSE: To study how the photoreceptoral and postreceptoral ON- and OFF-components contribute to the photopic sine-wave flicker ERG in the monkey by isolating the components with glutamate analogs. METHODS: Monkey photopic flicker ERGs were elicited with sine wave stimuli (mean luminance, 2.66 log cd/m(2); 80% modulation depth, on a 40 cd/m(2) white background) and were recorded for stimulus frequencies of 4 Hz to 64 Hz, before and after intravitreal injection of DL-2-amino-4-phosphonobutyric acid (APB) and cis-2, 3-piperidinedicarboxylic acid (PDA) that block ON- and OFF-bipolar activity, respectively. The amplitude and phase of the fundamental component were analyzed. RESULTS: The flicker response amplitudes increased after APB, for frequencies of 6 Hz to 32 Hz. The further addition of PDA to isolate the photoreceptor component resulted in a relatively small residual response that decreased monotonically from 4 Hz to 32 Hz. The postsynaptic APB (ON-) and PDA (OFF-) sensitive components were isolated by subtraction and were characterized by amplitude and phase vectors. The ON- and OFF-components were larger than the initial control responses for stimuli of 8 Hz to 40 Hz. These two components had a frequency-dependent phase difference of 160 degrees to 230 degrees; normally, they interfere with each other and reduce their net contribution. The phase difference between ON- and OFF-components was nearly 180 degrees for a 10-Hz stimulus, and the phase cancellation caused a prominent dip in amplitude at this frequency. CONCLUSIONS: These results indicate that postreceptoral ON- and OFF-components contribute substantially to the sine-wave flicker ERG, especially at higher stimulus frequencies. Because of phase cancellation, they mask each other in the net response in a frequency dependent fashion. The photoreceptor contribution is greater than the net postsynaptic component only for frequencies of approximately less than or equal to 10 Hz. These results can be summarized by a vector model that may be useful for interpreting changes resulting from retinal disease.

Adaptation, Ocular↗
PubMed1995

Role of hypothermia in the mechanism of protection against serotonergic toxicity. I. Experiments using 3,4-methylenedioxymethamphetamine, dizocilpine, CGS 19755 and NBQX.

High doses of 3,4-methylenedioxymethamphetamine (MDMA) have been shown to cause long-lasting depletions of central serotonin (5-HT) which are indicative of neuronal toxicity. The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (DZ) attenuates depletions of 5-HT induced by MDMA. Because DZ has been shown to induce hypothermia in rat models of ischemia, the purpose of this study was to assess whether DZ and two other glutamate antagonists, CGS 19755 (CGS) and 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), protect against MDMA-induced 5-HT depletions by induction of hypothermia. Male Sprague-Dawley rats were injected with either saline (SAL), DZ (2.5 mg/kg), CGS (25.0 or 50.0 mg/kg x 2 injections) or NBQX (30.0 mg/kg x 2 injections or 55.0 mg/kg x 3 injections) followed by either MDMA (40.0 mg/kg) or SAL. Core body temperature (TEMP) was monitored for 4 h or longer using radiotelemetry. Base-line TEMP was between 37.0 and 37.6 degrees C. Administration of DZ with MDMA decreased TEMP to 34.0 +/- 0.39 degrees C within 2 h of the MDMA injection, and also protected against serotonergic toxicity. Neither SAL/MDMA nor DZ/SAL had an effect on TEMP over the same period. When rats were treated with DZ/MDMA and TEMP was maintained between 38.4 degrees C and 40.4 degrees C for 4 h, protection against 5-HT depletion was abolished. Coadministration of the competitive NMDA antagonist CGS with MDMA-resulted in a decrease in TEMP to 34.5 +/- 0.27 degrees C, and provided partial protection against 5-HT depletions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

NMDA receptor antagonists influence early development of GABAergic interneurons in the mammalian striatum.

Neurotransmitters influence a wide variety of developmental processes. We hypothesize that N-methyl-D-aspartate (NMDA) glutamate receptors influence proliferation of populations of forebrain neurons. As our model, we use a subclass of GABAergic striatal interneurons that express the calcium binding protein parvalbumin (PV). To separate proliferative and post-proliferative effects of NMDA receptor antagonists on PV neurons, we first determined the birth-date of rat striatum PV neurons at the coronal level selected for analysis. Dividing striatal progenitor cells were marked by intraperitoneal injections of 5'-bromodeoxyuridine (BrdU) given to timed pregnant rats at selected time points between embryonic days (E) 12-22. Double immunohistochochemistry for BrdU and PV was used in adult progeny to determine the time course of neurogenesis of striatal PV neurons. The results of the neurogenetic analysis were then used for rational timing of treatment with competitive (CGS 19755) and non-competitive (MK-801) NMDA receptor antagonists. In comparison to pair-fed and vehicle-injected controls, gestational rats given CGS-19755 and MK-801 during the proliferative phase (E15-E18) showed a marked reduction of striatal PV neuron cell density as adults. In contrast, animals given NMDA antagonists during the post-proliferative period (E18-E21) showed no significant reduction in PV neuron cell density compared to pair-fed controls. These results suggest that glutamate influences cell proliferation of a population of striatal neurons by an NMDA-mediated mechanism, providing evidence for a novel role for excitatory amino acids in early forebrain development.

Animals↗
PubMed2000

Neuromuscular blocking agents in neurointensive care.

INTRODUCTION: Intensive care treatment of patients with severe head injury is aimed at preventing secondary injury. One of the cornerstones in this treatment is sedation and ventilation. Use of Neuromuscular Blocking Agents (NBA) has gained widespread use as part of the protocol for maintaining normal intracranial pressure values, without class 1 evidence for the efficacy of the treatment. METHODS: We examined data of the use of NBA as infusion during ventilator treatment, and IntraCranial Pressure (ICP) measurements in the database from the international multicenter randomized double blind trial of the NMDA receptor antagonist Selfotel. No specific mode of sedation was recommended in the study protocol. RESULTS: Of the 427 patients enrolled in the study 326 had a full data set, 138 received NBA during their stay in the ICU. There were no statistical difference in demographic data between the two groups. During their stay in the ICU, patients who received NBA had a median of 13.5 hours with a recorded ICP above 20 mm Hg, patients who did not receive NBA had a median of 6.5 hours with ICP above 20 mm Hg (p < 0.05). CONCLUSION: Our data challenges the concept of using NBA as part of a routine sedation strategy in treatment of patients with severe head injury.

Adult↗
PubMed1984

Gamma-D-glutamylglycine and cis-2,3-piperidine dicarboxylate as antagonists of excitatory amino acids in the hippocampus.

The actions of gamma-D-glutamylglycine (DGG) and cis-2,3-piperidine dicarboxylate (PDA) were studied in thin hippocampal sections of the guinea pig by intracellular recording. DGG and PDA suppressed depolarizations induced in CA3 neurons by short pulses of L-aspartate (Asp), D-homocysteate (DH) or L-glutamate (Glu). Asp- and DH-responses were more susceptible to the antagonists than were Glu-responses. The sensitivity difference between Glu-responses and Asp- or DH-responses was not so pronounced that these antagonists could be used to differentiate between Glu-mediated and Asp-mediated synapses. Glu and Asp pulses induced long hyperpolarizing deflections in some neurons. In about half of these neurons, PDA and DGG were without effect on the hyperpolarizing responses. The depolarizing action of gamma-amino butyric acid was unaffected by DGG and PDA. These antagonists blocked excitatory postsynaptic potentials induced by fimbrial stimulation. These results suggest that DGG and PDA are relatively specific antagonists of excitatory amino acids in the hippocampus, and that Glu (or Asp) is the neurotransmitter released from axons of CA3 neurons.

Amino Acids↗
PubMed1996

Comparison of the patterns of altered cerebral glucose utilisation produced by competitive and non-competitive NMDA receptor antagonists.

Recent studies indicate that competitive and non-competitive NMDA receptor antagonists can be readily distinguished by their effects on local cerebral glucose utilisation (1CGU). In the present study we compare the effects of the novel NMDA antagonist, (+)-1-methyl-1phenyl-1,2,3,4-tetrahydroisoquinoline (FR115427) on 1CGU, comparing its metabolic profile with that of the non-competitive NMDA receptor antagonist, dizocilpine (MK801) and of the competitive NMDA receptor antagonist CGS19755, using the 2-deoxyglucose metabolic mapping approach. Local cerebral glucose utilisation was measured in 80 anatomically discrete regions of the conscious rat brain using [14C]2-deoxyglucose quantitative autoradiography. Studies were initiated 10 min after the administration of FR115427 (0.1-3 mg/kg i.v.; n = 20), dizocilpine (0.03-0.3 mg/kg; n = 15), CGS19755 (1-30 mg/kg; n = 15) or saline (2 ml/kg; n = 5). Dizocilpine produced characteristic alterations in 1CGU with widespread increases in 1CGU in primary olfactory and limbic areas while reducing 1CGU in somatosensory and motor cortex. FR115427 produced a pattern of altered 1CGU which was broadly similar to that elicited by dizocilpine with increases in 1CGU in the pontine nuclei, presubiculum and hippocampus and reductions in somatosensory and motor cortex and within components of the auditory system. However, FR115427 was approximately 30-fold less potent than dizocilpine in this regard. In limbic structures, the effects of FR115427 were less pronounced than those produced by dizocilpine. Increases in 1CGU of 62-98% were found in retrosplenial, piriform and entorhinal cortex of dizocilpine-treated rats whereas these areas appeared relatively unaffected following FR115427 administration. A comparison of the pattern of metabolic response produced by each of these agents was performed by constructing a hierarchy of regional responsiveness using the f statistic: while focal differences in the metabolic profiles of dizocilpine and FR115427 were evident, a plot of the regional f values for dizocilpine and FR115427 revealed a strong overall relationship between the metabolic responses with a Pearson's product moment correlation of 0.78. In contrast, the correlation between the patterns produced by CGS19755 and that for dizocilpine or FR115427 was poor (r = 0.28 and 0.5 respectively).

Animals↗
PubMed1988

Possible role of excitatory amino acids in the convulsant action of catechol.

The effects of several excitatory amino acid receptor antagonists on sensory-evoked electromyographic activity induced by catechol have been studied in urethane-anaesthetised rats. 2-Amino-5-phosphono-valearic acid (1.2 mumol/kg i.c.), cis-2,3-piperidine dicarboxylic acid (1.4 mumol/kg i.c.), gamma-D-glutamyl-glycine (2.0 mumol/kg i.c.), 2-amino-7-phosphono-heptanoic acid (230 mumol/kg i.v.) and MK-801 (5 mg/kg i.p.) all significantly decreased the frequency of occurrence of those components of the sensory evoked EMG dependent on supraspinal structures, but were without effect on the spinal component.

2-Amino-5-phosphonovalerate↗
PubMed1991

Effects of NMDA receptor ligands on sensorimotor gating in the rat.

Pre-pulse inhibition of the acoustic startle response is a model of reflex modification which is thought to reflect sensorimotor gating mechanisms and is sensitive to disruption by non-competitive N-methyl-D-aspartate (NMDA) antagonists such as phencyclidine. The effects of two competitive antagonists, 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) (3-30 mg/kg) and cis-4-phosphonomethyl-2-piperidine-carboxylate (CGS 19755) (1-10 mg/kg), the non-competitive NMDA antagonist dizocilpine (0.5 mg/kg), and NMDA itself (1-30 mg/kg) were studied in the pre-pulse inhibition model. Rats were exposed to sessions in which 122 dB[A] startle-eliciting stimuli were presented either alone or preceded by weak 80 dB[A] prepulses with durations of 3, 10 and 30 ms, which under control conditions reduced the magnitude of the startle response. Neither NPC 12626 nor CGS 19755 produced disruption of pre-pulse inhibition as normally observed with phencyclidine-like drugs. NMDA also did not affect pre-pulse inhibition. As in previous experiments, dizocilpine produced a significant disruption of pre-pulse inhibition at all pre-pulse durations. These data suggest that actions at the phencyclidine binding site, and not the NMDA site, are responsible for the disruption of pre-pulse inhibition by phencyclidine-like drugs, and support reports of differences in the behavioral effects of competitive and noncompetitive NMDA antagonists. The effects of phencyclidine-like drugs on pre-pulse inhibition may represent a useful pharmacological model of schizophrenia-like cognitive deficits.

Acoustic Stimulation↗
PubMed1994

Enhancement of thrombolytic efficacy of tissue-type plasminogen activator by adjuvants in the guinea pig thrombosis model.

Reocclusion following thrombolysis is a major limitation of thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA). We investigated the effects of vapiprost ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-7-(5-((1,1'-biphenyl)-4-yl-methoxy)- 3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, a thromboxane A2 receptor antagonist); argatroban ((2R,4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfon yl] - L-arginyl)]-2-piperidine-carboxylic acid, a specific thrombin inhibitor) and MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid, a specific leukotriene biosynthesis inhibitor) on the thrombolytic efficacy of rt-PA. The guinea pig femoral artery was thrombotically occluded by photochemical reaction between rose bengal and green light. Thirty min after the occlusion, rt-PA was administered and the time (T1) for reopening of the vessel and the frequency of reocclusion (Fro) 24 h after thrombolysis were monitored. With rt-PA alone, T1 was 28 +/- 7 min (n = 10) and Fro was 70%. T1 was reduced to 9 and 20 min by a combination of rt-PA with vapiprost and argatroban respectively. Fro was reduced by all three adjuvants. Histological observations revealed extensive adherence of polymorphonuclear leucocytes to the damaged endothelium at the site of thrombolysis. It is concluded that thromboxane A2, thrombin and leucocytes are involved in reocclusion after thrombolysis.

Adjuvants, Pharmaceutic↗