cgp-37849 and 2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline

Mechanism of ictogenesis of D- and L-stereroisomers of homocysteic acid was studied in 12-day-old rats by means of antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. There was no qualitative difference between the two stereoisomers in generation of emprosthotonic (flexion) as well as generalized tonic-clonic seizures. Moderate differences were observed in the first, nonconvulsive effects of the two isomers. As generation of the two types of seizures is concerned, NMDA and AMPA participate in generalized tonic-clonic seizures whereas NMDA receptors play a dominant role in generation of flexion seizures.

Topics: 2-Amino-5-phosphonovalerate; Animals; Benzodiazepines; Dizocilpine Maleate; Homocysteine; Male; Quinoxalines; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures; Stereoisomerism

The involvement of glutamate system (particularly the NMDA and AMPA receptors) in the mechanism of antidepressant activity was demonstrated in preclinical and clinical studies.. In the present study, we investigated the effect of NMDA and AMPA receptors' ligands (agonists and antagonists) on the antidepressant-like activity of escitalopram, milnacipran, imipramine and reboxetine in the forced swim test in mice.. Antidepressant activity (reduction in immobility time) of escitalopram and milnacipran but not of imipramine and reboxetine was antagonized by N-methyl-D-aspartate acid. CGP37849 (antagonist of the NMDA receptor) enhanced the antidepressant activity of all examined antidepressants. On the other hand, CX614 (a potentiator/positive allosteric modulator of the AMPA receptor) enhanced the antidepressant activity of imipramine and reboxetine but not of escitalopram and milnacipran in this test. NBQX (the AMPA receptor antagonist) did not influence the antidepressant activity of all tested agents.. The data indicate the complex interactions following the activation or blockade of the NMDA and AMPA receptors with antidepressant drugs. The general phenomenon is the enhancing effect of the NMDA receptor antagonism on the antidepressant activity. Moreover, is can be concluded that the activity of antidepressants with a serotonergic mechanism of action can be inhibited by NMDA activation, while antidepressants with a noradrenergic mechanism of action are dependent on AMPA receptor transmission.

Topics: 2-Amino-5-phosphonovalerate; Animals; Antidepressive Agents; Citalopram; Cyclopropanes; Imipramine; Immobility Response, Tonic; Male; Mice; Milnacipran; Morpholines; Motor Activity; N-Methylaspartate; Oxazines; Quinoxalines; Reboxetine; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

The NMDA receptor antagonist, CGP 37849-induced reduction in immobility time in the forced swim test in mice was not antagonized by pre-treatment with the AMPA receptor antagonist NBQX. This is the first demonstration of the antidepressant effect of the NMDA antagonist not being dependent on the AMPA transmission.

Topics: 2-Amino-5-phosphonovalerate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Antidepressive Agents; Depressive Disorder; Excitatory Amino Acid Antagonists; Mice; Motor Activity; N-Methylaspartate; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Swimming

Cytosolic calcium ion concentrations ([Ca(2+)](i)) were measured in rat neocortical synaptosomes using fura-2, and depolarization of synaptosomal membranes was induced by K(+) (30 mM). The release of the endogenous excitatory amino acids glutamate and aspartate was evoked by K(+) (50 mM) and determined by HPLC. The release of [(3)H]-noradrenaline from rat neocortical synaptosomes or slices was evoked by K(+) (15 and 25 mM) and measured by liquid scintillation counting. Gabapentin produced a concentration-dependent inhibition of the K(+)-induced [Ca(2+)](i) increase in synaptosomes (IC(50)=14 microM; maximal inhibition by 36%). The inhibitory effect of gabapentin was abolished in the presence of the P/Q-type Ca(2+) channel blocker omega-agatoxin IVA, but not by the N-type Ca(2+) channel antagonist omega-conotoxin GVIA. Gabapentin (100 microM) decreased the K(+)-evoked release of endogenous aspartate and glutamate in neocortical slices by 16 and 18%, respectively. Gabapentin reduced the K(+)-evoked [(3)H]-noradrenaline release in neocortical slices (IC(50)=48 microM; maximal inhibition of 46%) but not from synaptosomes. In the presence of the AMPA receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2, 3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide (NBQX), gabapentin did not reduce [(3)H]-noradrenaline release. Gabapentin did, however, cause inhibition in the presence of the NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849). Gabapentin is concluded to reduce the depolarization-induced [Ca(2+)](i) increase in excitatory amino acid nerve terminals by inhibiting P/Q-type Ca(2+) channels; this decreased Ca(2+) influx subsequently attenuates K(+)-evoked excitatory amino acid release. The latter effect leads to a reduced activation of AMPA receptors which contribute to K(+)-evoked noradrenaline release from noradrenergic varicosities, resulting in an indirect inhibition of noradrenaline release.

Topics: 2-Amino-5-phosphonovalerate; Acetates; Amines; Animals; Aspartic Acid; Calcium; Cyclohexanecarboxylic Acids; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Gabapentin; gamma-Aminobutyric Acid; Glutamates; Male; Neostriatum; Neurons; Neurotransmitter Agents; Norepinephrine; omega-Agatoxin IVA; omega-Conotoxin GVIA; Potassium; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Synaptosomes; Tritium

To investigate whether in the prefrontal cortical (PFC) pyramidal cells, focal glutamate application to the apical dendrite induces bursting and whether the effect of glutamate involves activation of both NMDA and non-NMDA receptors.. Pyramidal cells in layers V and VI of the PFC were visualized in rat brain slices using infrared videomicroscopy and recorded with whole-cell electrodes. Glutamate and its agonists were focally applied to the apical dendrite and the soma using microiontophoresis.. Dendritic glutamate application (0-20 nA, 10 mmol/L) induced repetitive bursts in most cells tested (12/17). In the same cells, somatic glutamate (5-20 nA, 10 mmol/L) induced only regular spiking. The bursting effect is likely to be direct since applications 5 microns away from the dendrite resulted in either a much reduced effect or no effect. Both CGP 37849 1 mumol/L and NBQX 1 mumol/L reduced the effect, suggesting an involvement of both NMDA and non-NMDA receptors. However, when non-NMDA receptors were selectively activated using AMPA (2-50 nA, 10 mmol/L), only regular spiking was observed. In contrast, selective NMDA receptor activation (NMDA 1.3-25 nA, 100 mmol/L) reliably induced bursting.. In most PFC pyramidal cells tested, dendritic glutamate application induces repetitive bursting, whereas somatic glutamate application induces only regular spiking. Both NMDA and non-NMDA receptors are activated during dendritic glutamate application. However, bursting is primarily mediated by NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; Action Potentials; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Dendrites; Glutamic Acid; Male; N-Methylaspartate; Prefrontal Cortex; Pyramidal Cells; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Seizures were induced in immature 18-day-old rats by i.p. administration of homocysteine (11 mmol/kg) and the effects of selected antagonists of NMDA receptors [MK-801 (0.5 mg/kg), AP7 (0.33 mmol/kg), CGP 40116 (10 mg/kg)] and non-NMDA receptors [GDEE (4 mmol/kg), NBQX (two doses, 30 mg/kg each)] were studied. The effect of MgSO4 (two doses, 2 mmol/kg each) was also tested. The anticonvulsant effect was evaluated not only from the behavioral manifestations of seizures, but also in terms of some indicators of brain energy metabolism. Rat pups were sacrificed during generalized clonic-tonic seizures, corresponding to 16-45 min after homocysteine administration. Comparable time intervals were used for sacrificing the pups which had received the protective drugs. In contrast to neonatal rats, in which only NMDA antagonists could prevent homocysteine-induced seizures, both NMDA and non-NMDA receptor antagonists exerted an anticonvulsant effect in 18-day-old rats. In addition, the pronounced anticonvulsant effect could be achieved by the combined treatment with low subthreshold doses of NMDA (MK-801) and non-NMDA (NBQX) receptor antagonists. The protection was evident not only in suppressing behavioral symptoms of seizures, but also in preventing most of the metabolic changes accompanying seizures, mainly glycogen degradation. More than a sevenfold accumulation of lactate occurring during seizures was markedly reduced by all the tested drugs, but was not completely eliminated. All antagonists, when given alone in the same doses as those used for seizure protection, remained without any effect on lactate levels. Comparison of the present data with previous findings concerning neonatal rats suggests that there may be a developmental change in anticonvulsant efficacy of non-NMDA receptor antagonists against homocysteine-induced seizures in rats.

Topics: 2-Amino-5-phosphonovalerate; Age Factors; Animals; Anticonvulsants; Behavior, Animal; Brain Chemistry; Dizocilpine Maleate; Dose-Response Relationship, Drug; Energy Metabolism; Excitatory Amino Acid Antagonists; Glutamates; Homocysteine; Male; Neuroprotective Agents; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Studies in which glutamate (GLU) neurotransmission has been reduced at striatal synapses have shown that GLU influences the biosynthesis of certain peptide cotransmitters by striatal neurons. The present experiment was designed to test the effects of direct activation of the NMDA or AMPA types of GLU receptor on the levels of two mRNAs that encode the peptide cotransmitters met5-enkephalin (ME) and substance P (SP). In situ hybridization histochemistry of forebrain tissue sections from rats 8 h after a single intracerebroventricular infusion of NMDA or AMPA revealed a significant and dose-dependent elevation (to a maximum of almost 50%) of striatal ME mRNA when compared to vehicle-injected controls. SP mRNA was not significantly affected. NMDA was more effective than AMPA over the dose range used. Pretreatment with a potent and highly specific AMPA antagonist (NBQX) predictably blocked the AMPA-mediated elevation, and was only slightly effective against the NMDA-induced response. In striking contrast, pretreatment with a potent and highly selective NMDA antagonist (CGP37849) fully opposed both the NMDA- and the AMPA-mediated elevation of ME mRNA. These data further implicate the NMDA receptor in the regulation of peptide cotransmitter gene transcription. They suggest also that the AMPA receptor may play an indirect, synergistic role in the genetic responses of striatal neurons to GLU transmission.

Topics: 2-Amino-5-phosphonovalerate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Autoradiography; Corpus Striatum; Dose-Response Relationship, Drug; Enkephalin, Methionine; Enkephalins; Excitatory Amino Acid Antagonists; Histocytochemistry; In Situ Hybridization; Injections, Intraventricular; Male; N-Methylaspartate; Prosencephalon; Protein Precursors; Quinoxalines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Substance P

This study examined the interaction between various glutamate antagonists and selective D1 (SKF 38393) and D2 (RU 24213) dopamine agonists in the production of locomotion in the reserpine-treated mouse. Firstly, in normal mice, the NMDA channel blocker MK 801 (0.1-1.6 mg/kg) caused a biphasic stimulation/depression of locomotor activity, whereas the competitive NMDA antagonists CGP 40116 (0.25-8 mg/kg) and CPP (0.2-20 mg/kg), and the NMDA glycine site antagonist HA 966 (0.4-10 mg/kg) inhibited locomotion monophasically. These compounds caused varying degrees of muscle weakness and impairment of posture and gait, whilst the AMPA receptor blocker NBQX (0.2-25 mg/kg) had no significant effect on unconditioned mouse motor behaviour. None of the antagonists reversed reserpine-induced akinesia by themselves, but they all potentiated the locomotor movements induced by 30 mg/kg SKF 38393. Movements remained fluent with low doses of CPP, HA 966 and NBQX, but became ataxic with MK 801 and CGP 40116, with sedation prevailing at high doses of all the antagonists, as in normal mice. CPP and NBQX also combined synergistically with SKF 38393 to promote tonic convulsions. By contrast, RU 24213-induced locomotion was dose-dependently depressed by MK 801, CGP 40116 and HA 966, but was unaffected by CPP or NBQX. These differential effects of NMDA and AMPA antagonists on D1 and D2 motor responding in the monoamine-depleted mouse are discussed in terms of possible mechanisms and sites of action within the brain, and the implications for their putative use as adjuvants to L-dopa in antiparkinson therapy.

Topics: 2-Amino-5-phosphonovalerate; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Dizocilpine Maleate; Dopamine Agonists; Male; Mice; Mice, Inbred Strains; Motor Activity; Phenethylamines; Piperazines; Pyrrolidinones; Quinoxalines; Receptors, AMPA; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Reserpine

An assortment of glutamate antagonists with differing selectivities for NMDA and AMPA-type glutamate receptors, were tested for their effects in the mouse pilocarpine model of complex partial seizures. MK 801 (0.1-0.8 mg/kg) and high doses of HA 966 (50 mg/kg) were proconvulsant, whilst CGP 40116 (1-8 mg/kg) and low doses of HA 966 (0.4-10 mg/kg) inhibited pilocarpine-induced convulsions. CPP (5-20 mg/kg) and NBQX (1-50 mg/kg) were without effect. The dopamine D1 agonist SKF 38393 (10 mg/kg) facilitated the convulsant effects of low-dose pilocarpine (100 mg/kg). MK 801 (0.1-0.2 mg/kg) and HA 966 (50 mg/kg) interacted synergistically with SKF 38393 to promote the proconvulsant effects of D1 stimulation, whilst CPP (10-20 mg/kg) and HA 966 (10 mg/kg) had the opposite effect. CGP 40116 and NBQX were without effect. These results show that the convulsant qualities of MK 801 and SKF 38393, that have been detected in animal models of Parkinson's disease, can be reproduced in the pilocarpine model of epilepsy. Whilst the glutamate antagonists all interact synergistically with SKF 38393 to improve its antiparkinson activity, only MK 801 and high doses of HA 966 similarly potentiate the convulsions associated with D1 stimulation. An appropriate mixture of a glutamate antagonist and a D1 agonist could theoretically be used beneficially in the treatment of Parkinson's disease, without causing epilepsy as a side effect.

Topics: 2-Amino-5-phosphonovalerate; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Dizocilpine Maleate; Dopamine Agents; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Mice; Mice, Inbred Strains; Pilocarpine; Piperazines; Pyrrolidinones; Quinoxalines; Receptors, AMPA; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; Seizures

Sound-induced seizures in genetically epilepsy-prone rats were used to compare the anticonvulsant effect of phenytoin and diazepam with compounds which decrease glutamatergic neurotransmission including excitatory amino acid antagonists acting at N-methyl-D-aspartate (NMDA) receptors: D(-)CPPene, CGP 37849 and MK 801 or at the glycine/NMDA site: ACPC (1-aminocyclopropane-dicarboxylic acid) (partial agonist) or non-NMDA receptors: NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]-quinoxaline.Li) and GYKI 52466 (1-(aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepin e.HCl) or acting at sodium channels to decrease glutamate release: lamotrigine and BW 1003C87 (5(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonate). ED50 values against clonic seizures (in mumol/kg at the time of peak anticonvulsant effect) were: phenytoin 30.5 (2 h), diazepam 0.5 (0.5 h), MK 801 0.01 (4 h), D(-)CPPene 1.9 (4 h), CGP 37849 2 (1 h), GYKI 52466 24 (0.25 h), NBQX 40 (0.5 h), ACPC 1053 (0.5 h), BW 1003C87 2.2 (1 h), lamotrigine 4.8 (4 h). BW 1003C87, lamotrigine, MK 801, phenytoin, diazepam and CGP 37849 had the most favourable therapeutic indices (rotarod locomotor deficit ED50/anticonvulsant ED50).

Topics: 2-Amino-5-phosphonovalerate; Acoustic Stimulation; Amino Acids; Amino Acids, Cyclic; Analysis of Variance; Animals; Anticonvulsants; Behavior, Animal; Diazepam; Disease Models, Animal; Dizocilpine Maleate; Epilepsy; Female; Lamotrigine; Male; Motor Activity; Phenytoin; Pyrimidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Time Factors; Triazines

The effect of different glutamate-receptor antagonists on the induction of cortical spreading depression of Leao and of cortical anoxic membrane depolarization were investigated in the anaesthetized rat. Spreading depression (SD), elicited by mechanical stimulation of the cortical surface, was inhibited by the non-competitive N-methyl-D-aspartate (NMDA)-receptor blocker, (+-)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclo-hepten-5,10-imi ne maleate (dizocilpine or MK-801), (0.30 mumol kg-1 (0.10 mg kg-1)), and the competitive NMDA-receptor antagonists; cis-4-phosphonomethyl-2-piperidine carboxylate (CGS 19755), (3.36 mumol kg-1 (0.75 mg kg-1)), D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), (1.20 mumol kg-1 (0.25 mg kg-1)) and its carboxylester CGP 43487, (6.30 mumol kg-1 (1.50 mg kg-1)). The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepripriate (AMPA)-receptor blocker, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F) quinoxaline (NBQX), administered as an intravenous dose of 29.76 and 89.29 mumol kg-1 (10 & 30 mg kg-1), which is sufficient to block seizures and protect against ischaemic brain damage, did not inhibit spreading depression. None of the drugs utilized inhibited the anoxic membrane depolarization. The data demonstrate that NMDA-receptor activation is essential for the initiation and propagation of spreading depression, while activation of AMPA-receptors is not obligatory. The observed initiation and propagation of SD, during AMPA-receptor blockade, suggest that activation of voltage-operated ion channels may contribute to release the magnesium block of the NMDA-receptor operated channel and to the initiation of SD.

Topics: 2-Amino-5-phosphonovalerate; Animals; Brain; Cell Membrane Permeability; Cortical Spreading Depression; Dizocilpine Maleate; Electrophysiology; Excitatory Amino Acid Antagonists; Ion Channels; Male; Pipecolic Acids; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate

Glutamatergic transmission is an important factor in the development of neuronal death following transient cerebral ischemia. In this investigation the effects of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists on neuronal damage were studied in rats exposed to 10 min of transient cerebral ischemia induced by bilateral common carotid occlusion combined with hypotension. The animals were treated with a blocker of the ionotropic quisqualate or alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor, 2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), given postischemia as an intraperitoneal bolus dose of 30 mg kg-1 followed by an intravenous infusion of 75 micrograms min-1 for 6 h, or with the noncompetitive NMDA receptor blocker dizocilpine (MK-801) given 1 mg kg-1 i.p. at recirculation and 3 h postischemia, or with the competitive NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), 5 mg kg-1, given intraperitoneally at recirculation. Treatment with NBQX provided a significant reduction of neuronal damage in the hippocampal CA1 area by 44-69%, with the largest relative decrease in the temporal part of the hippocampus. In neocortex a significant decrease in the number of necrotic neurons was also noted. No protection could be seen following postischemic treatment with dizocilpine or CGP 40116. Our data demonstrate that AMPA but not NMDA receptor antagonists decrease neuronal damage following transient severe cerebral ischemia in the rat and that the protection by NBQX may be dependent on the severity of the ischemic insult. We propose that the AMPA receptor-mediated neurotoxicity could be due to ischemia-induced changes in the control mechanisms of AMPA receptor-coupled processes or to changes of AMPA receptor characteristics.

Topics: 2-Amino-5-phosphonovalerate; Animals; Blood Glucose; Blood Pressure; Body Temperature; Cell Death; Dizocilpine Maleate; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Quinoxalines; Rats; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

Excitatory amino acids are implicated in the development of neuronal cell damage following periods of reversible cerebral ischemia or insulin-induced hypoglycemic coma. To explore the importance of glutamate receptor activation in the posthypoglycemic phase, we exposed rats to 20 min of insulin-induced severe hypoglycemia. The rats were treated immediately after the hypoglycemic insult with four regimes of glutamate receptor antagonists: (1) the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propriate)-receptor antagonist NBQX [2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline] given as a bolus dose of 30 mg.kg-1 i.p., followed by an i.v. infusion of 225 micrograms.kg-1.min-1 for 6 h; (2) the non-competitive NMDA-receptor antagonist, dizocilpine (MK-801) 1 mg.kg-1 given i.v.; (3) a combined NBQX treatment, (a bolus dose of 10 mg.kg-1 i.p., followed by an i.v. infusion of 225 micrograms.kg-1.min-1 for 6 h), with dizocilpine 0.33 mg.kg-1 given twice i.p. at 0 and 15 min after recovery and (4) the competitive NMDA-receptor blocker CGP 40,116 [D-(E)-2-amino-4-methyl-5-phosphono-3- pentenoic acid] 10 mg.kg-1 given i.p. In the striatum, all glutamate receptor blockers significantly decreased neuronal damage by approximately 30%. An approximately 50% decrease in neuronal damage was demonstrated in neocortex and hippocampus following the combined treatment with NBQX and dizocilpine, while protection was variable following the treatment with a single glutamate-receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2-Amino-5-phosphonovalerate; Animals; Blood Pressure; Brain Ischemia; Cell Death; Dizocilpine Maleate; Electroencephalography; Excitatory Amino Acid Antagonists; Insulin Coma; Male; Necrosis; Neurons; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate