fg-9041 and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic-acid

The present study investigates the effects of injections of a specific N-methyl-D-aspartic acid (NMDA) antagonist 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phophonic acid (CPP) into the prefrontal cortex (PFC) on the extracellular concentrations of dopamine and acetylcholine in the nucleus accumbens (NAc) and on motor activity in the freely moving rat.. Sprague-Dawley male rats were implanted with guide cannulas into the medial PFC and NAc to perform bilateral microinjections and microdialysis experiments. Spontaneous motor activity was monitored in the open field.. Injections of CPP (1 microg/0.5 microL) into the PFC produced a significant increase of the baseline extracellular concentrations of dopamine (up to 130%), dihydroxyphenylacetic acid (DOPAC; up to 120%), homovanillic acid (HVA; up to 130%), and acetylcholine (up to 190%) in the NAc as well as motor hyperactivity. In the NAc, perfusion of the NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate antagonists CPP (50 microM)+6,7-dinitroquinoxaline-2,3-dione (DNQX; 50 microM) through the microdialysis probe blocked acetylcholine release, but not DOPAC and HVA increases produced by CPP injections into the PFC. Also, increases in motor activity produced by prefrontal injections of CPP were significantly reduced by bilateral injections into the NAc of a mixed D1/D2 antagonist, flupenthixol (5 and 25 microg/0.5 microL). Injections into the NAc of the muscarinic antagonist scopolamine (1 and 10 microg/0.5 microL) further increased, and of the nicotinic antagonist mecamylamine (1 and 10 microg/0.5 microL) did not change, the increases in motor activity produced by prefrontal CPP injections.. These results suggest that the dysfunction of NMDA receptors in the PFC could be a key factor in the neurochemical and motor effects associated with corticolimbic hyperactivity.

Topics: 3,4-Dihydroxyphenylacetic Acid; Acetylcholine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Cholinergic Antagonists; Dopamine; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Flupenthixol; Glutamic Acid; Homovanillic Acid; Injections, Intraventricular; Male; Mecamylamine; Microinjections; Motor Activity; Muscarinic Antagonists; N-Methylaspartate; Nicotinic Antagonists; Nucleus Accumbens; Piperazines; Prefrontal Cortex; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; Scopolamine

A recent study showed that cocaine-induced sensitization is associated with an increase in GABA (gamma-aminobutyric acid) transmission in the medial prefrontal cortex. Since previous studies have demonstrated that sensitization is associated with enhanced medial prefrontal cortex glutamatergic transmission, the present study examined the role of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate (AMPA/KA) receptors in cocaine-induced increases in medial prefrontal cortex GABA levels. Male Sprague-Dawley rats received four daily injections of saline (1 ml/kg, i.p.) or cocaine (15 mg/kg). One day later, animals were infused with NMDA or AMPA/KA antagonists 3-[(R)-2 carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) and 6,7-dinitroquinoxaline-2,3-dione (DNQX), respectively, into medial prefrontal cortex via microdialysis probe for 60 min before receiving systemic challenge injections of saline or cocaine. Cocaine-sensitized animals showed an increase in extracellular medial prefrontal cortex GABA levels that was blocked by prior medial prefrontal cortex infusion of DNQX, but not CPP. These data indicate that enhanced medial prefrontal cortex GABA transmission seen in cocaine-sensitized animals involves glutamatergic stimulation of AMPA receptors.

Topics: Analysis of Variance; Animals; Chromatography, High Pressure Liquid; Cocaine; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Male; Microdialysis; Motor Activity; Piperazines; Prefrontal Cortex; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate

Extraretinal projections onto neurons in the dorsal lateral geniculate nucleus (dLGN) play an important role in modifying sensory information as it is relayed from the visual thalamus to neocortex. The dLGN receives dopaminergic innervation from the ventral tegmental area; however, the role of dopamine in synaptic transmission in dLGN has not been explored. In the present study, whole cell recordings were obtained to examine the actions of dopamine on glutamatergic synaptic transmission. Dopamine (2-100 microm) strongly suppressed excitatory synaptic transmission in dLGN relay neurons that was evoked by optic tract stimulation and mediated by both N-methyl-d-aspartate and non-N-methyl-d-aspartate glutamate receptors. In contrast, dopamine did not alter inhibitory synaptic transmission arising from either dLGN interneurons or thalamic reticular nucleus neurons. The suppressive action of dopamine on excitatory synaptic transmission was mimicked by the D(2)-like dopamine receptor agonist bromocriptine (2-25 microm) but not by the D(1)-like receptor agonist SKF38393 (10-25 microm). In addition, the dopamine-mediated suppression was antagonized by the D(2)-like receptor antagonist sulpiride (10-20 microm) but not by the D(1)-like receptor antagonist SCH23390 (5-25 microm). The dopamine-mediated decrease in evoked excitatory postsynaptic current amplitude was accompanied by an increase in the magnitude of paired-pulse depression. Furthermore, dopamine also reduced the frequency but not the amplitude of miniature excitatory postsynaptic currents. Taken together, these data suggest that dopamine may act presynaptically to regulate the release of glutamate at the retinogeniculate synapse and modify transmission of visual information in the dLGN.

Topics: Anesthetics, Local; Animals; Animals, Newborn; Bromocriptine; Dopamine; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Antagonists; Geniculate Bodies; In Vitro Techniques; Neurons; Patch-Clamp Techniques; Piperazines; Presynaptic Terminals; Pyridazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Synaptic Transmission; Tetrodotoxin; Visual Pathways

Stroke-induced lesions of the insular cortex in the brain have been linked to autonomic dysfunction (sympathoexcitation) leading to arrhythmogenesis and sudden cardiac death. In experimental models, systemic estrogen administration in male rats has been shown to reduce stroke-induced cell death in the insular cortex as well as prevent sympathoexcitation. The central nucleus of the amygdala has been postulated to mediate sympathoexcitatory output from the insular cortex. We therefore set out to determine if endogenous estrogen levels within the central nucleus of the amygdala are altered following stroke and if microinjection of estrogen into the central nucleus of the amygdala modulates autonomic tone. Plasma estrogen concentrations were not altered by middle cerebral artery occlusion (22.86+/-0.14 pg/ml vs. 21.24+/-0.33 pg/ml; P>0.05). In contrast, estrogen concentrations in the central nucleus of the amygdala increased significantly following middle cerebral artery occlusion (from 20.83+/-0.54 pg/ml to 76.67+/-1.59 pg/ml; P<0.05). Local infusion of an aromatase inhibitor, letrozole, into the central nucleus of the amygdala at the time of middle cerebral artery occlusion prevented the increase in estrogen concentration suggesting that this increase was dependent on aromatization from testosterone. Furthermore, bilateral microinjection of estrogen (0.5 microM in 200 nl) directly into the central nucleus of the amygdala significantly decreased arterial pressure and sympathetic tone and increased baroreflex sensitivity, and these effects were enhanced following co-injection with either an N-methyl-D-aspartate or non-N-methyl-D-aspartate receptor antagonist. Taken together, the results suggest that middle cerebral artery occlusion resulted in synthesis of estrogen within the central nucleus of the amygdala and that this enhanced estrogen level may act to attenuate overstimulation of central nucleus of the amygdala neurons to prevent middle cerebral artery occlusion-induced autonomic dysfunction.

Topics: Amygdala; Animals; Aromatase Inhibitors; Autonomic Nervous System; Blood Pressure; Brain Chemistry; Estradiol; Estrogen Antagonists; Estrogens; Excitatory Amino Acid Antagonists; Fulvestrant; Heart Rate; Infarction, Middle Cerebral Artery; Injections, Intraventricular; Letrozole; Male; Microdialysis; Nitriles; Piperazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Synaptic Transmission; Testosterone; Triazoles

The present study was done to determine if estrogen interacts with excitatory and/or inhibitory amino acid neurotransmitters to alter neuronal excitability within the parabrachial nucleus (PBN) and modulate autonomic tone. First, the role of estrogen in modulating autonomic tone was investigated in male rats anesthetized with Inactin (100 mg/kg). Animals were instrumented to record blood pressure, heart rate, vagal parasympathetic and renal sympathetic nerve activities as well as baroreflex sensitivity. Direct, bilateral injection of 17beta-estradiol (0.5 microM; 200 nl/side) into the PBN resulted in a significant decrease in blood pressure (17+/-4 mmHg), sympathetic tone (20+/-5%) and heart rate (22+/-5 beats/min) while increasing parasympathetic tone (34+/-4%) 30 min post-injection. These estrogen-induced effects were completely blocked by the co-injection of estrogen with the estrogen receptor antagonist, ICI 182,780 (20 microM; 200 nl/side). Co-injection of the NMDA receptor antagonist, (+/-)-3-(2-carboxypiperazine-4-yl) propyl-1-phosphonic acid (CPP; 10 microM; 200 nl/side), with estradiol resulted in complete blockade of the estrogen-induced decrease in heart rate and increase in parasympathetic tone only. Co-injection of estradiol with the GABA(A) receptor antagonist, (+)-bicuculline (0.1 microM; 200 nl/side), resulted in complete blockade of the estrogen-induced decrease in blood pressure and sympathetic nerve activity only. These results suggest that estrogen acts on estrogen receptors on neurons in the PBN to modulate GABA(A)-receptor mediated inhibitory neurotransmission to alter sympathetic tone and blood pressure and on neurons in a separate, parallel pathway to modulate NMDA-receptor mediated neurotransmission to alter parasympathetic tone and heart rate.

Topics: Animals; Autonomic Nervous System; Baclofen; Baroreflex; Bicuculline; Blood Pressure; Cardiotonic Agents; Dose-Response Relationship, Drug; Drug Interactions; Estradiol; Estrogen Antagonists; Estrogens; Excitatory Amino Acid Antagonists; Fulvestrant; GABA Antagonists; Heart Rate; Male; Membrane Potentials; Phenylephrine; Piperazines; Pons; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Time Factors

In a previous study it was shown that nitroprusside-induced hypotension strongly enhances the release of dopamine (DA) in the prefrontal cortex (PFC). In the present study we have further investigated the mechanism involved in this effect. Glutamate receptor antagonists were infused into the ventral tegmental area (VTA) or PFC, while DA release was measured in the ipsilateral PFC and hypotension was applied by intravenous infusion of nitroprusside. Infusion into the VTA of neither a NMDA receptor antagonist (CPP), nor a non-NMDA antagonist (DNQX) affected the hypotension-induced increase of DA in the PFC. Intracortical infusion of CPP also failed to affect significantly, whereas local infusion of DNQX inhibited the hypotension-enhanced release of DA dose-dependently. The stimulation of DA release was relatively small in the VTA as well as in the nucleus accumbens when compared with the response in the PFC. It is concluded that DA released from mesocortical neurons can be modulated by two different mechanisms: first, by glutamate afferents to the VTA that modify the nerve-impulse flow of DA neurons; and, second, by glutamate afferents to the PFC that act at the level of the DA nerve terminals. The behaviour context (arousal or stress versus hypotension) determines which type of interaction predominates.

Topics: Animals; Dopamine; Excitatory Amino Acid Antagonists; Glutamic Acid; Handling, Psychological; Hypotension; Male; Microdialysis; Nitroprusside; Nucleus Accumbens; Piperazines; Prefrontal Cortex; Presynaptic Terminals; Quinoxalines; Rats; Rats, Wistar; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Ventral Tegmental Area

We have investigated the effects of perfusion of the N-methyl-D-aspartate (NMDA) receptor antagonist 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) on the endogenous glutamate-evoked changes of extracellular dopamine and alpha-aminobutyric acid (GABA) in the nucleus accumbens of the awake rat. Local infusion of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxilic acid in the nucleus accumbens produced an increase in extracellular concentrations of glutamate, dopamine, and GABA. At the dose of 4 mM, the increase of extracellular glutamate, dopamine, and GABA were 3.73 +/- 0.46 microM (n = 8; p < 0.001), 4.70 +/- 0.92 nM (n = 6; p < 0.001) and 0.36 +/- 0.08 microM (n = 8; p < 0.001), respectively. Perfusion of the NMDA-receptor antagonist CPP attenuated the increases of dopamine by 90% (n = 5; p < 0.001), but enhanced the increases of GABA by 70% (n = 7; p < 0.01). Perfusion of the AMPA-receptor antagonist DNQX did not attenuate the increases of GABA. These results suggest a differential mediation of ionotropic glutamatergic receptors in the actions of endogenous glutamate on extracellular concentration of dopamine and GABA.

Topics: Animals; Dicarboxylic Acids; Dopamine; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Male; Neurotransmitter Uptake Inhibitors; Nucleus Accumbens; Piperazines; Pyrrolidines; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate

Although the long-term neurobiological and behavioral effects of nigrostriatal lesions are well characterized, the events occurring soon after injury are not. These acute events can provide insight into the mechanisms underlying long-term adaptations to nigrostriatal lesions. The present experiments examined the basal ganglia immediate-early gene response to infusions of the catecholamine neurotoxin 6-hydroxydopamine into the nigrostriatal pathway in rats. Following 6-hydroxydopamine infusions into the medial forebrain bundle in awake, behaving rats, there was a rapid and transient induction of striatal c-fos and zif/268 messenger RNAs. Both immediate-early genes were maximally induced by 45min post-infusion, and returned to control levels by 1.5h (c-fos) or 3h (zif/268) post-infusion. Double-labeling experiments revealed that striatal c-fos expression occurred preferentially in preproenkephalin-expressing neurons. 6-Hydroxydopamine-induced c-fos messenger RNA was also observed in the substantia nigra pars reticulata and entopeduncular nucleus, but not the globus pallidus, 45 min after medial forebrain bundle 6-hydroxydopamine infusions. Finally, the role of ionotropic striatal glutamate receptors in nigrostriatal injury-induced striatal c-fos was examined by combining medial forebrain bundle 6-hydroxydopamine infusions with intrastriatal glutamate antagonist infusions. Both the N-methyl-D-aspartate antagonist, (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, and the non-N-methyl-D-aspartate antagonist, 6,7-dinitroquinoxaline-2, 3-dione, blocked striatal induction of c-fos messenger RNA following 6-hydroxydopamine infusions into the medial forebrain bundle. These results provide evidence of rapidly developing, glutamate-dependent molecular responses in the basal ganglia which may contribute to some of the well-described long-term adaptations of this system to nigrostriatal injury.

Topics: Animals; Basal Ganglia; Behavior, Animal; Excitatory Amino Acid Antagonists; Gene Expression; Genes, Immediate-Early; Male; Medial Forebrain Bundle; Motor Activity; Oxidopamine; Piperazines; Quinoxalines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sensation; Time Factors

Group-I metabotropic glutamate receptors (mGluRs) are densely expressed in the medium-sized spiny projection neurons of the striatum. Activation of the group-I mGluRs in the rat striatum with a selective group-I agonist, 3,5-dihydroxyphenylglycine (DHPG), produced locomotion and stereotypical behavior.. This study was designed to evaluate dependence of DHPG-stimulated motor behaviors on the ionotropic glutamate receptors [N-methyl-D-aspartate (NMDA) and kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazoleprionic acid (AMPA)].. In chronically cannulated rats, effects on motor activity of DHPG injected into the dorsal striatum were examined in the presence or absence of the antagonists selective for NMDA or kainate/AMPA receptors.. Bilateral injections of DHPG (80 nmol) into the dorsal striatum induced a delayed locomotion followed by a prolonged stereotypical behavior characterized by the repetitive twitching movement of the head and forepaws. Blockade of NMDA receptors with intrastriatal injection of the NMDA receptor antagonist, (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 2.5 nmol), did not attenuate the behavioral changes induced by DHPG administration. Conversely, CPP unmasked an early onset of locomotion in response to DHPG injection as opposed to the delayed locomotion induced by DHPG in the absence of CPP. Pretreatment of rats with the kainate/AMPA receptor antagonist, 6,7-dinitroquinoxaline2,3-dione (DNQX, 10 nmol), had no effect on DHPG-stimulated behaviors. CPP administered alone sedated animals, whereas DNQX given alone did not alter spontaneous behavioral activity.. Motor stimulation induced by activation of the DHPG-sensitive group-I mGluRs in the striatum is independent upon co-activation of NMDA or kainate/AMPA receptors, since the NMDA or the kainate/AMPA receptor antagonist had no effect on DHPG-stimulated motor activity.

Topics: Animals; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glycine; Kainic Acid; Male; Microinjections; Motor Activity; N-Methylaspartate; Neostriatum; Neurons; Piperazines; Quinoxalines; Rats; Rats, Wistar; Receptors, Glutamate; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Resorcinols; Stimulation, Chemical

In the present study we investigate the effects of a specific glutamate reuptake blocker, L-trans-pyrrolidine-3,4-dicarboxylic acid (PDC), on extracellular concentrations of glutamine and glutamate in the striatum of the freely moving rat. Intracerebral infusions of PDC (1, 2 and 4 mM) produced a dose-related increase in extracellular concentrations of glutamate and a dose-related decrease in extracellular concentrations of glutamine. These increases in extracellular glutamate and decreases in extracellular glutamine were significantly correlated. To investigate the involvement of ionotropic glutamate receptors in the decreases of extracellular glutamine produced by PDC, N-methyl-D-aspartate (NMDA) receptor antagonist and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor antagonist were used. Perfusion of the NMDA receptor antagonist blocked the decrease of extracellular glutamine but had no effect on the increase of extracellular glutamate, both produced by PDC. Perfusion of the AMPA/kainate receptor antagonist attenuated the increase of extracellular glutamate and not only blocked the decrease of extracellular glutamine but also produced a significant increase of extracellular glutamine. The results reported in this study suggest that both NMDA and AMPA/kainate glutamatergic receptors are involved in the regulation of extracellular glutamine.

Topics: Amino Acid Transport System X-AG; Animals; ATP-Binding Cassette Transporters; Dicarboxylic Acids; Excitatory Amino Acid Antagonists; Glutamic Acid; Glutamine; Male; Piperazines; Pyrrolidines; Quinoxalines; Rats; Rats, Wistar; Receptors, Glutamate

To assess the role of striatal glutamatergic synapses in mediating sensorimotor orientation behavior, glutamate receptor antagonists were infused into the left striatum of awake rats and behavioral orientation to contralateral and ipsilateral stimuli were quantified. The AMPA-kainate antagonist, DNQX, and the NMDA antagonist, CPP, both induced a large asymmetry in responding, such that the rats oriented much less to stimuli presented contralateral to the antagonist infusions. Furthermore, intrastriatal glutamate antagonist infusions increased the occurrence of incorrect responses, or turning away from a contralaterally-presented stimulus. In a separate experiment, intrastriatal DNQX was shown to block kainic acid (KA)-induced Fos expression in the striatum, but not in adjacent cerebral cortex, suggesting that the diffusion of this drug is restricted to the striatum.

Topics: Acoustic Stimulation; Animals; Attention; Corpus Striatum; Excitatory Amino Acid Antagonists; Functional Laterality; Male; Orientation; Photic Stimulation; Piperazines; Quinoxalines; Rats; Touch

The excitatory amino acid glutamate has been shown to be toxic to a number of neuronal cell types both in vitro and in vivo. It has also been shown to be capable of controlling the development of neurons grown in vitro. Using time-lapse video microscopy techniques the effects of glutamate on the rate of neurite outgrowth and growth cone motility were examined on cultured mouse spinal cord neurons. Concentrations in the range of 1 to 100 microM caused a significant inhibition of neurite outgrowth and concentrations of 10 and 100 microM significantly inhibited growth cone activity. In addition it was shown that the kainate/AMPA receptor antagonist (+/-)3-(2-carbvoxypiperazin-4-yl)-propyl-l-phosphonic acid, but not the NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione, was capable of blocking the inhibitory actions of glutamate on both outgrowth and motility. These results show that, at least in the culture system employed, glutamate might have a role in regulating neuronal development and function.

Topics: Animals; Cell Movement; Cells, Cultured; Excitatory Amino Acid Antagonists; Glutamic Acid; Mice; Microscopy, Video; Neurites; Piperazines; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Spinal Cord

It is known that glutamatergic tracts activated from the pedunculopontine tegmentum represent a major input to the nucleus basalis magnocellularis. To establish the role of different ionotropic glutamate receptors in synaptic transmission in the basal forebrain, the pedunculopontine tegmentum was stimulated in urethane-anesthetized rats and the resulting increases in cortical acetylcholine release and desynchronization of the electroencephalogram were monitored. R(-)-3-(2-carboxypiperazine-4-yl)-propyl-I-phosphonic acid (CPP), an antagonist at N-methyl-D-aspartate-type glutamate receptors, and 6, 7-dinitroquinoxaline-2, 3-dione (DNQX), an antagonist at alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors, were delivered through a microdialysis probe placed in the basal forebrain. The N-methyl-D-aspartate antagonist preferentially inhibited cortical acetylcholine release, while the AMPA antagonist was more powerful in reducing desynchronization. A combination of both N-methyl-D-aspartate and AMPA antagonists abolished the increase in cortical acetylcholine release without reducing desynchronization. The dissociation between increased cortical acetylcholine release and electroencephalogram desynchronization suggests that the activity of corticopetal basal forebrain cholinergic neurons is neither necessary nor sufficient to produce electroencephalogram desynchronization. Rather, the nucleus basalis can probably affect the electroencephalogram by its projections to the thalamus. The reversal of the inhibitory effect of DNQX on the electroencephalogram by CPP may be due to the blockade of N-methyl-D-aspartate receptors on the GABAergic projection from the basal forebrain to the thalamus.

Topics: Acetylcholine; Animals; Basal Ganglia; Cerebral Cortex; Cortical Synchronization; Electroencephalography; Excitatory Amino Acid Antagonists; Female; Piperazines; Prosencephalon; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission

1. Treatment of cultured cerebellar granule cells for 3 min with N-methyl-D-aspartate (NMDA) resulted in a concentration-dependent elevation of cyclic GMP. However, neither kainate (KA) nor NMDA produced a concentration-dependent elevation of this nucleotide after exposing cells to the agonist for 60 min. 2. Unlike the case for cGMP, both KA and NMDA produced concentration-dependent elevations of glutamate for 60 min incubation. 3. The NMDA-induced elevations of cGMP and glutamate were blocked by selective NMDA receptor antagonists. 4. The selective KA/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, 6,7-nitroquinoxaline-2,3-dione (DNQX), blocked the KA-induced elevations of cGMP with 3-min exposures, but it augmented the response with 60-min exposures. However, the KA-induced release of glutamate was prevented by DNQX. 5. The KA/AMPA receptor antagonist, GYKI 52466, blocked all KA-induced responses regardless of the incubation times.

Topics: Anti-Anxiety Agents; Anticonvulsants; Benzodiazepines; Cerebellum; Cyclic GMP; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Kainic Acid; N-Methylaspartate; Neurons; Neurotoxins; Piperazines; Quinoxalines

The role of glutamate receptors in processing noxious sensory input from the cornea was assessed in barbiturate-anesthetized rats. Animals were treated with selective antagonists for N-methyl-D-aspartate or non-N-methyl-D-aspartate receptor subtypes prior to application of mustard oil to the corneal surface. Neural activation was estimated from the number of neurons that produced Fos, the protein product of the immediate early gene, c-fos, as detected by immunocytochemistry. Fos-positive neurons were found at two distinct regions of the spinal trigeminal nucleus: the subnucleus interpolaris/caudalis transition and the subnucleus caudalis/upper cervical cord transition. The number of Fos-positive neurons was reduced dose-dependently by the competitive N-methyl-D-aspartate receptor antagonist, 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (0.08-8 nmol, i.c.v.), or by the non-N-methyl-D-aspartate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (2.5-250 nmol, i.c.v.). The greatest reduction in Fos-positive cells was seen at the subnucleus caudalis/upper cervical cord transition after blockade of either receptor subtype. Combined blockade of N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors did not cause a further reduction in the number of Fos-positive neurons than was seen after the highest dose of either antagonist alone. Peripheral or central administration of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, had no effect on the number of Fos-positive neurons after corneal stimulation. These results suggest that corneal input to neurons at the subnucleus caudalis/upper cervical cord transition, and to a lesser extent, at the subnucleus interpolaris/subnucleus caudalis transition depends on excitatory amino acid transmission. Both N-methyl-D-aspartate and non-N-methyl-D-aspartate glutamate receptor subtypes, but not the formation of nitric oxide, contribute to the processing of acute corneal stimuli by central trigeminal neurons.

Topics: Animals; Cornea; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Immunohistochemistry; Injections, Intraventricular; Male; Medulla Oblongata; N-Methylaspartate; Neurons; Nitric Oxide Synthase; Nociceptors; Piperazines; Proto-Oncogene Proteins c-fos; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Solitary Nucleus; Trigeminal Nerve; Trigeminal Nucleus, Spinal

The behavioral effects of amphetamine and cocaine are generally considered to be the result of their indirect dopaminergic activity. Recent reports, however, suggest that the activity of the psychomotor stimulants involves not only the dopaminergic but also the glutamatergic system. In the present study the role of the glutamate system in the action of the stimulants was investigated in mice with the use of glutamatergic agonists and antagonists administered either intraperitoneally or intracranially into the striatum. CPP, an NMDA-type glutamate antagonist, given systemically or intrastriatally, blocked stereotypy induced by either amphetamine or cocaine. These results represent pharmacological evidence that the glutamate system is an essential component in the expression of the stereotypic effect of the psychomotor stimulants, and that a locus of this action of glutamate is in the striatum. These conclusions were supported further by the observation that NMDLA administered focally into the striatum caused stereotypy which was indistinguishable from that produced by either amphetamine or dopamine. Stereotypy induced by amphetamine injected into the striatum was blocked by CPP or sulpiride administered either systemically or directly into the striatum; in contrast, stereotypy induced by NMDLA given into the striatum was blocked by CPP but not by sulpiride, regardless of whether the antagonists were presented systemically or into the striatum. The data suggest that stereotypy induced by amphetamine or cocaine is mediated by a dopaminergic activation of a glutamatergic system within the striatum.

Topics: Amphetamine; Animals; Cocaine; Corpus Striatum; Dizocilpine Maleate; Male; Mice; Piperazines; Quinoxalines; Receptors, Dopamine; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior; Sulpiride

Anatomic and physiologic studies in the rat have shown projections from the hippocampal formation (HF) and mediodorsal (MD) thalamic nucleus to the medial prefrontal cortex (mPFC). The authors used multi-barrel iontophoresis to: confirm the neurotransmitter used in the projection from HF to mPFC; investigate the role of GABAergic inhibition in the regulation of this projection; and examine the functional convergence of projections from HF and MD onto single mPFC neurons. During HF stimulation, nine cells (6%) showed excitation followed by prolonged inhibition, 39 cells (26%) showed prolonged inhibition alone and 100 cells (68%) showed no clear response. In a further 12 cells that showed no predrug excitation to HF stimulation (representing 16% of the cells in this category), iontophoresis of the GABAA antagonist bicuculline methiodide (BMI) revealed excitatory responses. A total of six mPFC cells (38% of the cells showing excitatory responses to HF stimulation) showed convergent excitation to HF and MD thalamic (or adjacent paratenial nucleus) stimulation. Five out of eight (63%) of the predrug or BMI-revealed excitatory responses of mPFC neurons to HF stimulation were selectively decreased after AMPA antagonist iontophoresis (either CNQX or DNQX). These data confirm that the HF projection to prefrontal cortex is, at least in part, glutamatergic; suggest that the responses of mPFC neurons to activity in this HF pathway are regulated by GABAergic inhibition; and indicate that projections from HF and MD converge onto single mPFC neurons.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Baclofen; Bicuculline; Brain Mapping; Electric Stimulation; Electrophysiology; GABA-A Receptor Antagonists; GABA-B Receptor Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Limbic System; Male; Neurons; Organophosphorus Compounds; Piperazines; Prefrontal Cortex; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Thalamus

Excitatory amino acid receptors have been implicated in mediating pain. 3-((+-)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive N-methyl-D-aspartate (NMDA) antagonist and MK-801, a phencyclidine (PCP) ligand and non-competitive NMDA antagonist, were injected intrathecally in mice alone or in combination with 6,7-dinitroquinoxaline-2,3-dione (DNQX), a non-NMDA antagonist. When tested in the formalin model of pain, antinociception following CPP plus DNQX was greater than that after MK-801 plus DNQX in both the acute and tonic phases. These dissimilarities are not consistent with activity of CPP and MK-801 at the same sites in the spinal cord.

Topics: Animals; Dizocilpine Maleate; Formaldehyde; Injections, Spinal; Male; Mice; Pain; Pain Measurement; Piperazines; Quinoxalines; Receptors, N-Methyl-D-Aspartate

In anesthetized rats, the intrastriatal infusion of the delta-opioid receptor agonist, [D-Pen2,D-Pen5]enkephalin, increased the extracellular concentration of dopamine. This effect was abolished by the NMDA receptor antagonist, 3-[(+/-)-2-carboxypiperazine-4-yl]propyl-1-phosphonate, but was unchanged by the AMPA (D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and kainate receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione. This suggests that the dopamine release induced by the delta-opioid agonist depends critically on the involvement of glutamatergic transmission via NMDA receptors.

Topics: Analgesics; Analysis of Variance; Animals; Corpus Striatum; Dopamine; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Male; Piperazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate

The propagation of sustained potential shifts associated with spreading depression (SD) was studied by microelectrodes placed in diverse layers at different locations in hippocampus of anesthetized rats. SD was induced by raising interstitial potassium concentration ([K+]0) focally in the CA1 region of the dorsal hippocampus either by microdialysis or by microinjection. Recurrent waves of SD propagated from the dialysis site throughout the hippocampus. Potential shifts (delta V0) associated with SD usually began earlier and were always of larger amplitude and longer duration in stratum (st.) radiatum (layer of apical dendrites) than in st. pyramidale (layer of pyramidal cell somata). The velocity of propagation in the two layers differed and varied independently one from the other. When SD was provoked by orthodromic train stimuli, the apparent direction of propagation in st. pyramidale was opposite that in st. radiatum. Microinjection of high K+ solution was more likely to provoke SD when placed in the st. radiatum, 50-100 microns ventral to st. pyramidale, than in other cytoarchitectonic layers. In about half the trials after 30 to 90 min of high K+ dialysis, a prolonged depressed state developed during which the potential in st. radiatum shifted at irregular intervals between near-rest level and a strongly negative level, while delta V0 shifts in st. pyramidale were smaller and more irregular in amplitude. This state is termed prolonged unstable SD". When the NMDA receptor antagonist CPP was dialyzed together with high K+, the onset of SD was postponed and delta V0 waves propagated in st. pyramidale without corresponding waves in st. radiatum; less frequently the other way around.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dendrites; Dialysis; Electrophysiology; Female; Hippocampus; In Vitro Techniques; Microinjections; Neurons; Piperazines; Potassium; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Intrathecal (i.t.) injection of the competitive and selective N-methyl-D-aspartate (NMDA) receptor antagonists DL-2-amino-5-phosphonopentanoic acid (AP5), D-2-amino-7-phosphonoheptanoic acid (AP7), beta-D-aspartylaminomethyl phosphonic acid (Asp-AMP), 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and gamma-D-glutamylaminomethyl phosphonic acid (Glu-AMP) produced dose-dependent and reversible analgesic effects in the mouse hot-plate and formalin tests of nociception. They were slightly more potent in the formalin test but had no or negligible effects in the tail-flick test. The non-selective or non-NMDA receptor antagonists 6-cyano-7-nitro-quinoxalinedione (CNQX), 6,7-dinitro-quinoxalinedione (DNQX), gamma-D-glutamylglycine (gamma DGG), gamma-glutamylaminomethyl sulphonic acid (GAMS), kynurenic acid, cis-2,3-piperidine dicarboxylic acid (cis-PDA; partial agonist) and p-bromobenzoyl piperazine dicarboxylic acid (pBB-PzDA) had the same efficacy in the mouse hot-plate, tail-flick and formalin tests (gamma DGG and pBB-PzDA were not tested in the formalin test). This heterogeneous group of antagonists was somewhat more potent in the tail-flick test and slightly less potent in the formalin test than in the hot-plate test. Of the two glycine site antagonists tested, 7-chlorokynurenic acid (7-Cl-Kyn) and (+/-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), the effect of the latter was compatible with selective action at the NMDA receptor complex while the action of the former was comparable to those of non-selective excitatory amino acid (EAA) receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesics; Analysis of Variance; Animals; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Injections, Spinal; Ketamine; Male; Mice; Piperazines; Quinoxalines; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate; Serine

We tested the hypothesis that suppression of inward calcium current in presynaptic terminals is the cause of failure of synaptic transmission early during cerebral hypoxia. Postsynaptic responses in CA1 zone of hippocampal tissue slices were blocked either by the combined administration of 6,7-dinitroquinoxaline-2,3-dione (DNQX) and 3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP) or by lowering extracellular calcium concentration ([Ca2+]o). Repetitive orthodromic activation of central neurons caused transient decrease of [Ca2+]o (measured by ion selective microelectrodes) in neuropil, attributable to influx of Ca2+ in presynaptic terminals. Presynaptic [Ca2+]o responses were rapidly and reversibly suppressed when oxygen was withdrawn from hippocampal tissue slices. The 'resting' baseline level of [Ca2+]o declined at first gradually, then precipitously as in spreading depression (SD). Presynaptic volleys during high frequency train stimulation were also depressed somewhat before SD began. We conclude that (1) presynaptic Ca2+ currents fail during hypoxia, perhaps because 'resting' intracellular free Ca2+ activity is increased and, in part, also because of partial failure of presynaptic impulse conduction; (2) the influx of Ca2+ into brain cells in hypoxic spreading depression is not mediated by glutamate/aspartate dependent channels.

Topics: Action Potentials; Animals; Calcium; Calcium Channels; Electric Stimulation; Hippocampus; Hypoxia, Brain; In Vitro Techniques; Neurons, Afferent; Piperazines; Quinoxalines; Rats; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Synapses

We previously reported that systemic treatment with a noncompetitive antagonist affecting the NMDA subtype of excitatory amino acid (EAA) receptor, MK-801, inhibits photic induction of Fos-like immunoreactivity (Fos-lir) in the hamster suprachiasmatic nucleus (SCN). Because MK-801 blocks the Ca2+ channel associated with the NMDA receptor, it may also influence the activity of other transmitters acting through Ca2+ channels. To assess the specificity of these effects, we compared the effects on photic induction of Fos-lir of several treatments: central injection of a competitive NMDA antagonist, CPP; central injection of a non-NMDA antagonist, DNQX; and systemic injection of the non-competitive NMDA antagonist, ketamine. Fos-lir was induced in SCN cells of vehicle-injected hamsters exposed to a light pulse 4-5 h after dark onset. Pretreatment with CPP (greater than 2 nmoles) or ketamine (greater than 100 mg/kg) caused a dose-related inhibition of photic induction of Fos-lir in portions of the SCN. These treatments reduced Fos-lir mainly in the rostral SCN and ventrolateral, but not dorsolateral, portions of the caudal SCN. Pretreatment with DNQX (greater than 20 nmoles) also inhibited photic induction of Fos-lir in the same regions of the SCN. These results indicate that photic induction of Fos protein in a portion of the hamster SCN is regulated by both NMDA and non-NMDA types of EAA receptor.

Topics: Animals; Cricetinae; Evoked Potentials; Ketamine; Male; Mesocricetus; Oncogene Proteins v-fos; Optic Nerve; Photic Stimulation; Piperazines; Quinoxalines; Receptors, Amino Acid; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate; Suprachiasmatic Nucleus

Rat cerebellar granule cells, when subjected to a glucose-free environment for 4 h, developed extensive degeneration of neuronal cell bodies and their associated neurite network over the following 24 h. This neuronal damage was quantitated with a colorimetric assay using the metabolic dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. Hypoglycemic neuronal injury could be markedly reduced by the presence of both competitive (3-(+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) and non-competitive (phencyclidine) N-methyl-D-aspartate receptor antagonists, but not by kainate/quisqualate preferring antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and 6,7-dinitroquinoxaline-2,3-dione. Glucose deprivation neuronal injury was also reduced by adding glutamate-degrading enzymes to the incubation medium. Monosialoganglioside GM1, but not its asialo derivative (lacking sialic acid), was also effective in protecting against hypoglycemic neurodegeneration when included during the period of glucose deprivation. These results suggest that the neuronal injury to cerebellar granule cells resulting from glucose deprivation is mediated predominantly by activation of the N-methyl-D-aspartate type of excitatory amino acid receptor, perhaps through the action of endogenously released glutamate. Furthermore, the monosialoganglioside GM1, a member of a class of naturally occurring sialoglycosphingolipids, is able to attenuate this neuronal injury--as already observed for glutamate neurotoxicity and anoxic neuronal death in cerebellar granule cells. Gangliosides may thus prove to be of therapeutic utility in excitatory amino acid-associated neuropathologies.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cerebellum; G(M1) Ganglioside; Gangliosides; Hypoglycemia; Nerve Degeneration; Neurons; Piperazines; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, Amino Acid; Receptors, Cell Surface; Receptors, N-Methyl-D-Aspartate

Perfusion with quisqualate (5 x 10(-6) M) and kainate (5 x 10(-7) M), selective agonists of glutamate receptors, enhanced the release of dopamine in both caudate and accumbens nuclei of freely-moving rats, measured by the transcerebral microdialysis technique. In contrast, N-methyl-D-aspartate (NMDA) did not affect dopamine release, except at very high concentrations (10(-2) M). The quisqualate-kainate antagonist, FG 9041 (DNQX), antagonized the elevation of dopamine release induced by quisqualate and, furthermore, reduced that of kainate. CPP, a selective NMDA antagonist, did not counteract the quisqualate- or kainate-induced stimulation of dopamine release. The enhancement of dopamine release after quisqualate and kainate was accompanied by behavioural stimulation characterized by grooming, rearing, hypermotility with sniffing and confined sniffing. This behavioural syndrome could be blocked by haloperidol. Conversely, perfusion with NMDA did not activate behaviour even at high concentrations. These results indicate that the dopaminergic system, within the caudate and the accumbens nuclei, is under glutamatergic control through kainate and quisqualate receptors, while the NMDA receptors do not appear to be involved.

Topics: Animals; Behavior, Animal; Caudate Nucleus; Dialysis; Dopamine; Glutamates; Haloperidol; Kainic Acid; Male; N-Methylaspartate; Nucleus Accumbens; Piperazines; Quinoxalines; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, Glutamate; Receptors, Neurotransmitter

A dose-dependent, saturable, and calcium-dependent release of gamma-[3H]aminobutyrate [( 3H]GABA) from cortical neurones and D-[3H]aspartate from cerebellar granule cells following stimulation by a range of L-enantiomers of neuroactive acidic sulphur amino acids has been demonstrated. Moreover, the sulphur amino acid-evoked release of the transmitter amino acids was found to be sensitive to the presence of both selective N-methyl-D-aspartate and quisqualate/kainate receptor antagonists. Following the recent demonstration of an endogenous location for several of the acidic sulphur amino acids and their excitotoxic involvement in several neuropathological states and coupled with the knowledge that many important CNS connections are still undefined as far as their excitatory transmitter or transmitters are concerned, the present findings are of immediate importance in the continued search for endogenous excitatory amino acid agonists in addition to glutamate and aspartate.

Topics: Amino Acids; Amino Acids, Sulfur; Animals; Aspartic Acid; Calcium; Cells, Cultured; Cerebellum; Cerebral Cortex; gamma-Aminobutyric Acid; Kynurenic Acid; Mice; Neurons; Piperazines; Quinoxalines; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

The non N-methyl-D-aspartate (NMDA) receptor antagonists dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), both inhibit the visually driven response of sustained ganglion cells in the cat retina in vivo. In contrast to these findings, the potent NMDA receptor antagonist 3-[+/- )-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) has no effect. Thus, the endogenous excitatory amino acid released onto these cells on visual stimulation acts at non-NMDA receptors.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cats; In Vitro Techniques; Iontophoresis; Piperazines; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Retina; Retinal Ganglion Cells

The N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors has been well described as a result of the early appearance of NMDA antagonists, but no potent antagonist for the "non-NMDA" glutamate receptors has been available. Quinoxalinediones have now been found to be potent and competitive antagonists at non-NMDA glutamate receptors. These compounds will be useful in the determination of the structure-activity relations of quisqualate and kainate receptors and the role of such receptors in synaptic transmission in the mammalian brain.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Aspartic Acid; Binding, Competitive; Cell Membrane; Cerebral Cortex; Ibotenic Acid; Kainic Acid; Ketamine; N-Methylaspartate; Neurons; Piperazines; Quinoxalines; Rats; Receptors, AMPA; Receptors, Drug; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Spinal Cord