dizocilpine-maleate and selfotel

The growing number of cellular and molecular pathways believed to be involved in mechanisms of ischemic cell death in the brain has spurred a similar growth in the number of potential neuroprotective modalities, the majority of which are pharmacological in nature. Preventing or minimizing the first few steps in the cascade of events leading to ischemic cell death would have a more profound effect on the postischemic outcome than intervention at later steps in that cascade. This logic is, of course, at the heart of the urgency in providing the stroke or cardiac arrest patient with the earliest possible neuroprotective treatment. For the purpose of assessing potential neuroprotective modalities, the use of a well-established cerebral hypoxic/ischemic model system is a prerequisite. In our studies, we have used two major approaches, in vitro and in vivo. We evaluated both agonists and antagonists of ionotropic glutamate receptor channels (IGRC) and their effects in exacerbating and attenuating, respectively, the posthypoxic/ischemic outcome. Other drugs were tested for their ability to block the L-type voltage-sensitive calcium channels (VSCC), which are responsible for calcium influx and overload upon hypoxia/ischemia. These two membrane protein entities, the IGRC and the VSCC, are believed to be involved in the early stages of the cellular cascade that leads to the demise of neurons posthypoxia/ischemia. Some of the drugs were also tested for possible interaction with each other searching for possible synergy. These and other published studies in the field are reviewed here.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Diltiazem; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Hypoxia-Ischemia, Brain; Neuroprotective Agents; Pipecolic Acids; Rats; Receptors, Glutamate

Topics: Animals; Brain Ischemia; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Pipecolic Acids; Piperidines; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate

Topics: Animals; Arterial Occlusive Diseases; Calcium; Cell Survival; Cerebral Arterial Diseases; Cerebrovascular Disorders; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Humans; Intracranial Embolism and Thrombosis; Neurons; Pipecolic Acids; Receptors, N-Methyl-D-Aspartate; Tissue Plasminogen Activator; Tomography, Emission-Computed

The N-methyl-D-aspartate (NMDA) receptor has been recently identified as an important mediator of impulsive choice, as assessed in delay discounting. Although discounting is independently influenced by sensitivity to reinforcer magnitude and delayed reinforcement, few studies have examined how NMDA receptor ligands differentially affect these parameters.. The current study examined the effects of various NMDA receptor ligands on sensitivity to reinforcer magnitude and delayed reinforcement in a delay-discounting procedure.. Following behavioral training, rats received treatments of the following NMDA receptor ligands: the uncompetitive antagonists ketamine (0, 1.0, 5.0, or 10.0 mg/kg; i.p.), MK-801 (0, 0.003, 0.01, or 0.03 mg/kg; s.c.), and memantine (0, 2.5, 5.0, or 10.0 mg/kg; i.p.), the competitive antagonist CGS 19755 (0, 5.0, 10.0, or 20.0 mg/kg; s.c.), the non-competitive NR2B subunit-selective antagonist ifenprodil (0, 1.0, 3.0, or 10.0 mg/kg; i.p), and the partial agonist D-cycloserine (0, 3.25, 15.0, or 30.0 mg/kg; s.c.).. When an exponential model was used to describe discounting, CGS 19755 (5.0 mg/kg) increased impulsive choice without altering sensitivity to reinforcer magnitude. Conversely, ketamine (10.0 mg/kg), memantine (5.0 mg/kg), and ifenprodil (10.0 mg/kg) decreased sensitivity to reinforcer magnitude without altering impulsive choice. MK-801 and D-cycloserine did not alter delay-discounting performance, although two-way ANOVA analyses indicated D-cycloserine (15.0 mg/kg) decreased impulsive choice.. The behavioral changes observed in delay discounting following administration of NMDA receptor antagonists do not always reflect an alteration in impulsive choice. These results emphasize the utility in employing quantitative methods to assess drug effects in delay discounting.

Topics: Animals; Behavior, Animal; Choice Behavior; Cycloserine; Delay Discounting; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Impulsive Behavior; Ketamine; Ligands; Male; Memantine; Pipecolic Acids; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Reinforcement, Psychology

In this study, we investigate the effects of chronic administration of (-)nicotine on the function of the NMDA-mediated modulation of [(3)H]dopamine (DA) release in rat prefrontal cortex (PFC) and nucleus accumbens (NAc). In the PFC synaptosomes NMDA in a concentration-dependent manner evoked [(3)H]DA release in rats chronically treated with vehicle (14 days) with an EC(50) of 13.1 +/- 2.0 microM. The NMDA-evoked overflow of the [(3)H]DA in PFC nerve endings of rats treated with (-)nicotine was significantly lower (-43%) than in vehicle treated rats. The EC(50) was 9.0 +/- 1.4 microM. Exposure of NAc synaptosomes of rats treated with vehicle to NMDA produced an increase in [(3)H]DA overflow with an EC(50) of 14.5 +/- 5.5 microM. This effect was significantly enhanced in chronically treated animals. The EC(50) was 10.5 +/- 0.5 microM. The K(+)-evoked release of [(3)H]DA was not modified by the (-)nicotine administration. Both the changes of the NMDA-evoked [(3)H]DA overflow in the NAc and PFC disappeared after 14 days withdrawal. The results show that chronic (-)nicotine differentially affects the NMDA-mediated [(3)H]DA release in the PFC and NAc of the rat.

Topics: Analysis of Variance; Animals; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glycine; Male; N-Methylaspartate; Nicotine; Nicotinic Agonists; Nucleus Accumbens; Pipecolic Acids; Potassium; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Synaptosomes; Time Factors; Tritium

Brain glutamatergic system is involved in synaptic plasticity as a base for learning and neural development. This study investigated the effects of neonatal and adult chronic antagonism of N-methyl-d-aspartate (NMDA) receptors, a subtype of glutamate receptors, on learning and/or memory. Rats were trained in the radial-maze learning, which is known as a measure of spatial working memory capacities, in adulthood after neonatal or adult repeated treatment of MK-801 (dizocilpine; 5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine), a non-competitive antagonist, or neonatal repeated treatment of CGS 19755 (cis-4-phosphonomethyl-2-piperadine carboxilic acid), a competitive antagonist. Neonatal repeated treatment of MK-801 or CGS 19755 markedly impaired the radial-arm maze learning. In addition, the treatment altered activities differently in the radial-maze and in the open-field. On the other hand, adult repeated treatment with MK-801 affected neither the radial-maze learning nor activities. Results suggest that chronic blockade of NMDA receptors in a neonatal stage may produce long-lasting deteriorative effects on spatial working memory in adulthood.

Topics: Aging; Animals; Animals, Newborn; Brain; Brain Chemistry; Dizocilpine Maleate; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Exploratory Behavior; Female; Glutamic Acid; Learning Disabilities; Male; Maze Learning; Memory; Memory Disorders; Pipecolic Acids; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Time

The coexistence of nicotinic cholinergic receptors (nAChRs) and of N-methyl-D-aspartate (NMDA) receptors on the same noradrenergic axon terminals and the nAChR/NMDA receptor cross-talk were investigated by monitoring the release of noradrenaline (NA) evoked in superfused rat hippocampal synaptosomes by (-)-nicotine and NMDA alone or in combination. In medium containing a physiological concentration (1.2 mM) of Mg2+, the release of [3H]NA was very slightly increased by NMDA plus glycine, whereas it was significantly enhanced by (-)-nicotine. The (-)-nicotine/NMDA combination elicited supraadditive release which was totally abolished by the nAChR blocker mecamylamine and partly prevented by selectively blocking NMDA receptors. Supraadditive [3H]NA release was also observed by exposing synaptosomes to veratrine, but not to ionomycin. The supraadditive release elicited by the (-)-nicotine/NMDA or the veratrine/NMDA combination was sensitive to the protein kinase A/C inhibitor staurosporine and the selective protein kinase A inhibitor H89, but insensitive to the protein kinase C inhibitor Ro 31-8220. It is concluded that (i) release-modulating nAChRs and NMDA receptors coexist on hippocampal noradrenergic axon terminals; and (ii) nicotine permits NMDA receptor activation in the presence of Mg2+, possibly because the nicotine-induced influx of Na+ depolarizes the nerve ending membrane sufficiently to remove the Mg2+ block.

Topics: Animals; Calcium; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Male; Mecamylamine; N-Methylaspartate; Nerve Endings; Nicotine; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synaptosomes

Much evidence has been gathered to show that neurotoxicity of excitatory amino acids is mainly activated through an N-methyl-D-aspartate (NMDA) receptor cascade. We evaluated the protective effects of NMDA receptor antagonists, MK-801 and CGS19755 on spinal cord neurons using the NMDA receptor mediated neurotoxicity model in vivo.. New Zealand white rabbits underwent an infrarenal aortic isolation. Group A animals (n = 7) received segmental aspartate (50 mM) infusion for 10 minutes. Group B animals (n = 6) were pretreated with MK-801 (6mg/kg), a noncompetitive NMDA receptor antagonist, that was administrated intravenously for 3 hours beginning 1 hour before the segmental infusion of aspartate (50 mM) of 10 minutes. Group C animals (n = 6) received pretreatment with CGS19755 (30mg/kg), a competitive NMDA receptor antagonist, that was administrated in the same fashion as group B, followed by the segmental infusion of aspartate (50 mM). Neurologic status was scored at 12, 24, and 48 hours after operation using the Tarlov score. All the animals were sacrificed for histologic assessment at 48 hours.. Group A animals exhibited paraplegia or paraparesis with marked neuronal necrosis. Group B and C animals showed significantly better neurologic function compared with group A (p = 0.0013, A vs. B) (p = 0.0011, A vs. C). Pathohistological change was not observed in group B and C animals.. NMDA receptor antagonists can have protective effects on spinal cord neurons against aspartate induced neurotoxicity. This model may be useful in assaying protective agents in the spinal cord against neuronal injury mediated by NMDA receptors in vivo.

Topics: Animals; Aspartic Acid; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Neurons; Neuroprotective Agents; Paraplegia; Pipecolic Acids; Rabbits; Spinal Cord

Cannabinoids, as a result of their ability to activate cannabinoid CB1 receptors, have been shown to possess neuroprotective properties in vivo. In vitro studies into neuroprotective effects mediated by CB1 receptors have in general used primary neuronal cultures derived from embryonic rodents. In the present study, we have investigated whether embryonic chick telencephalon primary cultures in serum-free medium are a useful alternative for such in vitro studies. The CB agonist CP 55940 reduced the cAMP response to 5 microM forskolin by 40 and 50% at concentrations of 3 nM and 30 nM, respectively. This reduction was blocked by the CB1 receptor antagonist AM251, indicating the presence of functional CB1 receptors in the cultures. Incubation of the cultures with glutamate (100 microM or 1 mM) for 1 h followed by medium change and incubation for 24 h produced a release of the cytoplasmic enzyme lactate dehydrogenase into the medium. This release was prevented by MK-801 confirming the central role of NMDA receptors in the glutamate toxicity. However, 3-30 nM CP 55940 did not produce any neuroprotection in this model regardless as to whether dibutyryl cyclic AMP was added to the culture medium. The endocannabinoid anandamide was also without effect when added either per se or together with the related N-acyl ethanolamines palmitoylethanolamide, oleoylethanolamide and stearoylethanolamide (at relative concentrations matching those seen in rat brain after excitotoxic insult). It is concluded that embryonic chick neurons in primary serum-free culture are not a useful model for the study of neuroprotective effects mediated by CB1 receptors in vitro.

Topics: Animals; Arachidonic Acids; Cannabinoids; Cells, Cultured; Chick Embryo; Colforsin; Cyclic AMP; Cyclohexanols; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Combinations; Endocannabinoids; Excitatory Amino Acid Antagonists; Glutamic Acid; L-Lactate Dehydrogenase; Models, Animal; Neurons; Pipecolic Acids; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Telencephalon

Autoradiographical studies revealed that 10 nM [3H]N-acetyl-aspartyl-glutamate (NAAG) labelled grey matter structures, particularly in the hippocamus, cerebral neocortex, striatum, septal nuclei and the cerebellar cortex. The binding was inhibited by (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine (DCG IV), an agonist at group II metabotropic glutamate receptors (mGluR II). (RS)-alpha-Methyl-4-tetrazolylphenylglycine (MTPG), (RS)-alpha-cyclopropyl-4-phosphonoglycine (CPPG) and (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE), all antagonists at mGluR II and mGluR III, also inhibited [3H]NAAG binding. Other inhibitors were (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD), a broad-spectrum mGluR agonist with preference for groups I and II and the mGluR I agonists/mGluR II antagonists (S)-3-carboxy-4-hydroxyphenylglycine (3,4-CHPG) and (S)-4-carboxy-3-hydroxyphenylglycine (4,3-CHPG). Neither the mGluR I specific agonist (S)-dihydroxyphenylglycine nor any of the ionotropic glutamate receptor ligands such as kainate, AMPA and MK-801 had strong effects (except for the competitive NMDA antagonist CGS 19755, which produced 20-40% inhibition at 100 microM) suggesting that, at low nM concentrations, [3H]NAAG binds predominantly to metabotropic glutamate receptors, particularly those of the mGluR II type. Several studies have indicated that NAAG can interact with mGluR II and the present study supports this notion by demonstrating that sites capable of binding NAAG at low concentrations and displaying pharmacological characteristics of mGluR II exist in the central nervous tissue. Furthermore, the results show that autoradiography of [3H]NAAG binding can be used to quantify the distribution of such sites in distinct brain regions and study their pharmacology at the same time.

Topics: Alanine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Binding Sites; Brain; Brain Chemistry; Carboxypeptidases; Cold Temperature; Cycloleucine; Cyclopropanes; Dipeptides; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Female; Glutamate Carboxypeptidase II; Glycine; Kainic Acid; Male; Nerve Tissue Proteins; Phosphoserine; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Tetrazoles

The objective of this study was to investigate the effects of the HIV-1 envelope protein gp120 and its peptide fragments on the function of N-methyl-D-aspartate (NMDA) receptors mediating release of cholecystokinin (CCK) and somatostatin (SRIF). These are nonconventional NMDA receptors recently found to be activated by glycine or D-serine 'only'. The release of cholecystokinin-like immunoreactivity (CCK-LI) and of somatostatin-like immunoreactivity (SRIF-LI) elicited by 12 mM K+ from superfused rat neocortex synaptosomes was potently increased by gp120, its cyclic V3 loop and the linear V3 sequence BRU-C-34-A, but not by RP-135 (a central portion of BRU-C-34-A). The EC50 values of gp120 were 0.02 nM (CCK-LI release) and 0.01 nM (SRIF-LI release). The releasing effect of gp120 was prevented by blocking the glycine site or the ion channel of NMDA receptors, but not the glutamate recognition site; in addition, the gp120 effect was strongly inhibited by nanomolar concentrations of Zn2+ ions and by low micromolar concentrations of ifenprodil. It is concluded that gp120 acts as a very potent agonist at the glycine site of NMDA receptors sited on CCK- and SRIF-releasing nerve endings; the protein is able to activate the receptor channel in the absence of glutamate. Gp120 activates the receptors through its V3 loop as peptide fragments related to V3 retain near-maximal activity. The sensitivity of the gp120 effect to both Zn2+ and ifenprodil would not be incompatible with the idea that these NMDA receptors contain the triple subunit combination NR1/NR2A/NR2B.

Topics: 2-Amino-5-phosphonovalerate; Animals; Cerebral Cortex; Cholecystokinin; Dizocilpine Maleate; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; HIV Envelope Protein gp120; HIV-1; Indoles; Kynurenic Acid; Male; Maleimides; Neurons; Nitroarginine; Peptide Fragments; Pipecolic Acids; Piperazines; Piperidines; Potassium; Protein Structure, Tertiary; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Somatostatin; Synaptic Transmission; Synaptosomes; Zinc

N-Acetyl-aspartyl-glutamate (NAAG), an agonist at Group II metabotropic glutamate receptors (mGluR II), also activates the NMDA-type of ionotropic glutamate receptors and, at high micromolar concentrations, has previously been shown to induce neuronal cell death. In the present study we have morphologically quantified the neurotoxic action of intracerebroventricularly administered NAAG on the hippocampal formation and compared it to the action of the selective endogenous NMDA agonist quinolinic acid. Finally, we examined whether the action of NAAG can be modified by NMDA receptor antagonists and mGluR II ligands. NAAG-induced neurodegeneration was found to be less severe than that induced by quinolinate. It was prevented by inhibitors of NMDA receptors and also by an mGluR II agonist (DCG IV) but not by an mGluR II antagonist (EGlu).

Topics: Animals; Cell Death; Cerebral Ventricles; Dipeptides; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Injections, Intraventricular; Ligands; Male; Neurons; Neurotoxins; Pipecolic Acids; Quinolinic Acid; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate

Cortical afferents excite striatal efferent neurons through activation of N-methyl-D-aspartate (NMDA) receptors, which can be modulated by D2 dopamine receptors. It is suggested that activation of PKA by D2 receptor blockade leads to NMDA receptor phosphorylation in the dendrites or phosphorylation of transcription factors in the nucleus. Thus, the levels and cellular localization of activated PKA may determine if D2 antagonist-mediated gene expression is dependent on NMDA receptor activation. We have previously demonstrated that NMDA receptor antagonists block gene expression induced by a high dose of eticlopride in medial and central but not lateral striatum. Here, we examined the effects of NMDA receptor antagonists on striatal gene expression after administration of a low dose of eticlopride. The results showed that NMDA receptor antagonists blocked gene induction by eticlopride throughout striatum. Less PKA activation by the low dose of eticlopride might explain why the expression was more sensitive in the lateral striatum to NMDA receptor blockade than in our previous study. To increase levels of PKA activation to the extent that NMDA receptor blockade would have less effect on eticlopride-mediated gene induction in all regions of striatum, we administered the phosphodiesterase inhibitor IBMX to animals treated with eticlopride. The combined administration of IBMX and eticlopride induced gene expression that was only partially attenuated (c-fos) or unaffected (zif268) by NMDA receptor blockade. These data support the suggestion that the degree of second messenger activation by D2 receptor blockade determines whether D2 dopamine receptor antagonist-mediated gene expression is dependent on NMDA receptor activation.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Gene Expression; Genes, Immediate-Early; Male; Phosphodiesterase Inhibitors; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Salicylamides

An in vitro model of ischemia was developed and characterized using the acute rat hippocampal slice preparation. Neuroprotective concentrations of several competitive and noncompetitive glutamate subtype-selective antagonists (CGS-19755, MK-801, YM90K and GYKI-52466) were initially determined in anoxia-enhanced agonist-induced excitotoxicity experiments. Concentrations which proved to be effective in these studies were subsequently tested for their effectiveness against an ischemic episode. Ischemia was defined as a 30-min exposure to aglycemic media ending in 5 min of concurrent anoxia, a protocol which was arrived at by empirically determining the effect of various hypoglycemic and anoxic insults on the ability of hippocampal slices to retain their electrophysiological viability. Exposure to such an ischemic episode resulted in a loss of viability by most slices, an effect which was strongly dependent on extracellular calcium. AMPA antagonists applied alone produced no neuroprotective effect in the present model of in vitro ischemia, while NMDA antagonists applied alone had a modest neuroprotective effect. In contrast, the coapplication of 10 microM MK-801 and 300 microM GYKI-52466, noncompetitive NMDA and AMPA receptor antagonists, respectively, resulted in almost complete neuroprotection. This protection was comparable to that obtained by withholding extracellular calcium, indicating that the toxic effects of glutamate receptor overstimulation can be accounted for solely by calcium influx. The effect of this combination treatment on the survival rate of hippocampal slices was synergistic, that is greater than the sum of the effects of the individual compounds. The results indicate that neuroprotection against acute ischemic insults may require a combination therapy approach.

Topics: Animals; Anti-Anxiety Agents; Benzodiazepines; Brain Ischemia; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hypoxia; Male; Neuroprotective Agents; Pipecolic Acids; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

The effects of i.m. injections of (+)-HA-966, a glycine-site antagonist at the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, its enantiomer (-)-HA-966, the competitive glutamate antagonist CGS-19755, the uncompetitive glutamate antagonists phencyclidine and dizocilpine, and the micro opioid agonist morphine were evaluated in a repeated acquisition task in pigeons. All of the drugs produced dose-dependent decreases in rates of responding. The NMDA receptor and channel blockers and (+)-HA-966 appeared to have a greater effect on acquisition than did morphine at doses that did not fully suppress responding. The rate suppression and learning impairment produced by a large dose of (+)-HA-966 (100 mg/kg) were completely prevented by coadministration of the glycine-site agonist D-serine (560 mg/kg) but not by its enantiomer, L-serine (1000 mg/kg). D-Serine, however, produced incomplete antagonism of the effects of dizocilpine and phencyclidine and failed to alter those of CGS-19755. These findings provide evidence that reducing the activity of the NMDA subtype of the glutamate receptor through pharmacological action at any of three sites produces similar decrements in acquisition, and those produced through antagonism of the glycine site are differentially sensitive to the glycine-site agonist D-serine.

Topics: Animals; Central Nervous System; Columbidae; Conditioning, Operant; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Phencyclidine; Pipecolic Acids; Pyrrolidinones; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Serial Learning; Serine

Many laboratories have reported that coadministration of N-methyl-D-aspartate (NMDA) receptor antagonists with psychomotor stimulants prevents the development of behavioral sensitization and therefore concluded that NMDA receptor transmission is necessary for sensitization. According to an alternative "state-dependency" interpretation, NMDA receptor antagonists do not prevent sensitization. Rather, they become a conditioned stimulus for the sensitized response, i.e., it is only elicited in response to combined administration of the NMDA receptor antagonist and the stimulant. This hypothesis is supported by progressive augmentation of the locomotor response to the drug combination during the induction phase, and expression of sensitization when challenged with the combination but not the stimulant alone. To test this hypothesis, rats were treated during a 6-day induction phase with amphetamine (Amph) alone or in combination with the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg) or the non-competitive NMDA receptor antagonist MK-801 (0.05, 0.1 and 0.25 mg/kg). When CGS 19755 was coadministered with Amph, there was no progressive augmentation of response to the drug combination. When challenged with Amph alone, rats did not exhibit the biphasic pattern of locomotor activity characteristic of Amph sensitization. No sensitization of stereotyped behaviors was evident, although the ambulatory response was greater than that exhibited by naive rats. Results with MK-801 were complex, but progressive augmentation of response to the drug combination appeared to in part reflect sensitization to MK-801 and could be dissociated from the ability of MK-801 to prevent the development of sensitization as assessed by response to challenge with Amph alone. Many of these findings are inconsistent with predictions of the "state-dependency" hypothesis. Moreover, the ability of NMDA receptor antagonists to prevent biochemical and electrophysiological correlates of sensitization is difficult to reconcile with the idea that sensitization develops in the presence of NMDA receptor blockade but cannot be expressed. Together, these findings suggest that the ability of NMDA receptor antagonists to prevent Amph sensitization reflects a requirement for NMDA receptor transmission during its induction.

Topics: Amphetamine; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Hypersensitivity; Excitatory Amino Acid Antagonists; Male; Motor Activity; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sodium Chloride

Volume-sensitive organic anion channels (VSOACs) in astrocytes are activated by cell swelling and are permeable to organic anions, such as glutamate and taurine. We have examined the release of glutamate through VSOACs during the propagation of spreading depression (SD). SD was induced by bath application of ouabain in hippocampal brain slices and was monitored by imaging intrinsic optical signals, a technique that provides a measure of cellular swelling. The onset of SD was associated with increased light transmittance, confirming previous studies that cellular swelling occurs during SD. NMDA receptor antagonists, either noncompetitive (MK-801, 10-50 microM) or competitive (CGS-17355, 100 microM), reduced the rate of propagation of SD, indicating that glutamate release contributes to SD onset. SD still occurred in zero Ca(2+)-EGTA (0-Ca(2+)-EGTA) solution, a manipulation that depresses synaptic transmission. HPLC measurements indicated that, even in this solution, there was significant glutamate release. Two lines of experiments indicated that glutamate was released through VSOACs during SD. First, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), a blocker of VSOACs, depressed the rate of propagation of SD in a manner similar to NMDA antagonists. Second, NPPB inhibited the release of glutamate during SD in 0-Ca(2+)-EGTA external solution. These results indicate that cellular swelling during SD causes the activation of VSOACs and the release of glutamate by permeation through this channel. Cellular swelling is a result of neuronal activity and is observed during excitotoxicity. Therefore, glutamate release from VSOAC activation could occur under conditions of cell swelling and contribute to excitotoxic damage.

Topics: Animals; Anion Transport Proteins; Carrier Proteins; Chelating Agents; Cortical Spreading Depression; Dizocilpine Maleate; Egtazic Acid; Excitatory Amino Acid Antagonists; Furocoumarins; Glutamic Acid; In Vitro Techniques; Nitrobenzoates; Pipecolic Acids; Rats; Rats, Sprague-Dawley

In this study, we examined the acute anticonvulsant spectrum of (1) dizocilpine (0.03-3 mg/kg), CGS 19755 (1-10 mg/kg), and 7-chlorokynurenic acid (1-100 nmol) (NMDA receptor/ionophore complex antagonists); (2) muscimol (0.1-10 nmol; direct GABA(A) agonist); (3) YM90K (3-10 mg/kg; AMPA receptor antagonist); and (4) diazepam (2 and 5 mg/kg) and carbamazepine (5 and 20 mg/kg), two standard anticonvulsants, using the partially-kindled hippocampal model for epileptic seizures in freely moving rats. The anticonvulsant effect of these compounds were assessed by determining (1) the afterdischarge (AD), which is indicative of the severity of the seizure and related to seizure maintenance, and (2) the pulse number threshold (PNT), which is indicative of the seizure threshold or initiation. In addition, ataxia, a measure of CNS dysfunction, was assessed for each compound. Overall, our results indicated that the anticonvulsant compounds examined could be classified into three categories based on effects on the AD and PNT: (1) elevation of PNT (carbamazepine, dizocilpine, CGS 19755 and 7-chlorokynurenic acid); (2) reduction of AD (diazepam and muscimol); and (3) mixed action, i.e., increased PNT and decreased AD (YM90K). Behavioral data indicated that all compounds, except carbamazepine, produced a dose- or concentration-dependent ataxia. Overall, our results suggest that NMDA receptors play a role in seizure initiation, whereas the GABA(A) receptors appear to be involved in seizure maintenance and AMPA receptors may be involved in both phenomena.

Topics: Animals; Anticonvulsants; Ataxia; Carbamazepine; Diazepam; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; GABA Agonists; Hippocampus; Kynurenic Acid; Male; Muscimol; Pipecolic Acids; Quinoxalines; Rats; Rats, Wistar; Seizures

Recent clinical trials with non-competitive and competitive N-methyl-D-aspartate (NMDA) receptor antagonists in patients with stroke have shown that these patients develop more adverse effects, particularly psychomimetic effects such as hallucinations and agitation, than normal volunteers at equivalent doses. We therefore examined whether such increased adverse effect potential of NMDA antagonists also occurs in a rat model of permanent focal ischemia. For this purpose, the right middle cerebral artery was occluded under halothane anesthesia, and behavioral alterations in response to the non-competitive NMDA antagonist, MK-801 (dizocilpine), were recorded after recovery from anesthesia. Behavioral alterations in ischemic rats were compared with those in sham-lesioned rats in a blinded fashion. MK-801 (0.4 mg/kg) induced psychomimetic-like stereotyped behaviors which were about twice as intense in ischemic than in non-ischemic rats. A similar trend for enhanced adverse effects was seen with the competitive NMDA antagonist CGS 19755 (Selfotel). Although more NMDA antagonists have to be tested to draw definite conclusions, the present data may indicate that enhanced sensitivity of stroke patients to adverse effects of NMDA antagonists can be predicted by use of a focal ischemia model in rats, thus allowing use of this model for developing novel cytoprotective strategies targeted to minimize glutamatergic excitotoxicity with reduced adverse effect potential.

Topics: Animals; Behavior, Animal; Binding, Competitive; Brain; Brain Ischemia; Cerebrovascular Disorders; Dizocilpine Maleate; Injections, Intraperitoneal; Male; Pipecolic Acids; Piperazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate

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.

Topics: Animals; Antimetabolites; Bromodeoxyuridine; Cell Count; Cell Survival; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; gamma-Aminobutyric Acid; Immunohistochemistry; Interneurons; Male; Neostriatum; Parvalbumins; Pipecolic Acids; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Dopamine D1 receptor regulation of striatal gene expression is dependent on N-methyl-D-aspartate (NMDA) receptors. To determine whether pharmacologically distinct NMDA receptors are differentially involved, we examined the effects of different NMDA receptor antagonists on D1-induced immediate early gene expression. Systemic administration of the channel blocking antagonists MK-801 and dextrorphan and the competitive antagonist CGS 19755 blocked gene expression induced by the D1 agonist SKF 82958. The NMDA polyamine site antagonist ifenprodil, however, potentiated the effect of SKF 82958. Since ifenprodil is selective for receptors containing the NR2B subunit, the data suggest that subtypes of NMDA receptors may be differentially involved in regulating striatal function.

Topics: Animals; Corpus Striatum; Dextrorphan; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Genes, Immediate-Early; Male; Pipecolic Acids; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate

The interaction of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist YM90K with the competitive N-methyl-D-aspartate (NMDA) antagonist CGS19755 or with the NMDA channel blocker MK801 on the spatial memory of rats was examined by the 4-arm-baited radial maze task. When administered alone, these drugs had no effect on the spatial memory. The combination of YM90K and MK801 synergistically disrupted working and reference memories, whereas the combination of YM90K and CGS19755 had no effect. These results indicate that the blockade of the AMPA receptor and NMDA channels produces a synergistic impairment of spatial memory and suggest that interaction between the AMPA and NMDA receptors plays a role in cognitive function.

Topics: Animals; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory; Pipecolic Acids; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

The function of striatopallidal neurons is regulated by N-methyl-D-aspartate (NMDA) and dopamine D2 receptors. Previous studies show that immediate early gene induction by D2 receptor blockade is suppressed by NMDA receptor antagonists. Because the pharmacology of NMDA receptors depends on the incorporation of different NR2 subunits and NR2 subunits show regional and cellular differences in their expression in striatum, our study examined whether different NMDA receptor antagonists would have differential effects on eticlopride-induced immediate early gene expression in striatum. Male Sprague-Dawley rats were pretreated with vehicle, CGS 19755, MK-801 or ifenprodil. Rats then received injections of eticlopride and were killed 40 min later. In situ hybridization histochemistry was used to determine the expression of c-fos and zif268 in the striatum. Eticlopride increased immediate early gene expression in striatum, with the increase generally being greater in lateral than in medial striatum. Pretreatment with each of the NMDA receptor antagonists dose-dependently decreased the expression of the immediate early genes. This suppression of eticlopride-induced gene expression was significant only in the medial-central aspect of striatum. Although there was a trend toward suppression of the gene induction in lateral striatum, it did not reach statistical significance and was not typically dose dependent. The data suggest that different types of NMDA receptor antagonists do not exert differential effects on D2 dopamine receptor-mediated function in the striatum. In addition, the data indicate that eticlopride-induced gene expression in the striatum is not uniformly dependent on NMDA receptor activation.

Topics: Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Gene Expression; Genes, Immediate-Early; Male; Pipecolic Acids; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Salicylamides

Racemic (dl)-methadone has antagonist activity at the N-methyl-D-aspartate (NMDA) receptor. We evaluated dl-methadone, the opioid active (l-) and the opioid inactive (d-) isomers in competition binding assays. dl-Methadone and its d- and l- isomers exhibited low micromolar affinities for the [3H]MK-801-labeled non-competitive site of the NMDA receptor in both rat forebrain and spinal cord synaptic membranes, with Ki values and displacement curves similar to those of dextromethorphan, an established NMDA receptor antagonist. They lacked affinity at the [3H]CGS-19755-labeled competitive site of the NMDA receptor. Therefore, both methadone and its the d- and l- isomers differ from morphine, hydromorphone, and naltrexone in that they have non-competitive antagonist activity at the NMDA receptor. A non-opioid NMDA receptor antagonist, such as d-methadone, may improve the efficacy of morphine by attenuating the development of tolerance.

Topics: Animals; Binding Sites; Binding, Competitive; Dextromethorphan; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Isomerism; Male; Methadone; Pipecolic Acids; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Synaptic Membranes

The effects of N-methyl-D-aspartate NMDA receptor antagonists on scopolamine-induced amnesia and on delay-interposed short-term memory performance were investigated using an 8-arm radial maze in rats. Scopolamine, a muscarinic antagonist, deteriorated the radial maze performance, while MK-801, an NMDA receptor channel blocker and CGS-19755, a competitive NMDA receptor antagonist, showed no obstruction to the spatial cognition in the non-delayed maze task. MK-801 (0.01-0.03 mg/kg, i.v.) and CGS-19755 (1-10 mg/kg, i.v.) significantly augmented scopolamine-induced deficit in the non-delayed maze task and impaired the short-term memory in the 5-min delay-interposed task. These results suggest that NMDA antagonists have a negative action on short-term memory and that the interaction between the NMDA and the central muscarinic system plays a role in modulating the cognitive function.

Topics: Amnesia; Animals; Cholinergic Antagonists; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Learning Disabilities; Male; Maze Learning; Memory, Short-Term; N-Methylaspartate; Pipecolic Acids; Rats; Rats, Wistar; Scopolamine

To address the issue of the cytotoxicity of glutamate antagonists, we administered representative agents to rats and used HSP72 immunocytochemistry as a measure of neuronal injury in the brain. The doses studied spanned the reported neuroprotective range for each compound. Some, but not all, glutamate antagonists induce neuronal injury in the brain. The non-competitive NMDA antagonists (MK801 and dextrorphan) demonstrate maximum toxicity. Competitive NMDA antagonists (CGS 19755 and MDL 100,453) may or may not induce neuronal injury depending on the particular compound. The polyamine site (SL 82.0715-10) antagonist does not result in neuronal injury. Cingulate and retrosplenial cortex neurotoxicity is not a ubiquitous feature of neuroprotective agents that block excitotoxcity, but is limited to NMDA antagonists and may depend upon the duration and completeness of the blockade of the NMDA receptor.

Topics: Animals; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gyrus Cinguli; Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Immunohistochemistry; Male; Pipecolic Acids; Rats; Rats, Sprague-Dawley

We tested the hypothesis that the administration of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist 2R,4R,5S-(2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid) (NPC 17742) or cis-4-(phosphonomethyl) piperidine-2-carboxylic acid (CGS 19755) or the noncompetitive NMDA receptor antagonist dizocilpine (MK-801), at the appropriate doses, would all have efficacy in decreasing early postischemic brain injury in a feline model of transient focal ischemia.. Prospective, randomized, controlled animal trial.. University research laboratory.. Forty mixed-breed cats.. Halothane-anesthetized cats underwent 90 mins of left middle cerebral artery occlusion plus 4 hrs of reperfusion. At 75 mins of ischemia, control cats received intravenous saline (n = 10). Experimental cats (n = 10 in each group) were treated with NPC 17742 (5 mg/kg bolus and 2.5 mg/kg/hr throughout reperfusion), MK-801 (5 mg/kg intravenous bolus), or CGS 19755 (40 mg/kg intravenous bolus) in a randomized fashion.. Microsphere-determined blood flow to the ipsilateral inferior temporal cortex and caudate nucleus decreased to the same extent during ischemia, and recovered to the same extent during early reperfusion, in the four groups. Triphenyltetrazolium-determined injury volume of the ipsilateral caudate nucleus in cats treated with NPC 17742 (105 +/- 25 [SEM] mm3), MK-801 (97 +/- 22 mm3), and CGS 19755 (97 +/- 13 mm3) was less than in control cats (198 +/- 21 mm3). Hemisphere injury volumes with NPC 17742 (1209 +/- 405 mm3) and MK-801 (1338 +/- 395 mm3) were less than that value in controls (2193 +/- 372 mm3), whereas injury volume with CGS 19755 (1553 +/- 519 mm3) treatment did not attain significance (p < .09).. NMDA receptor activation during reperfusion may contribute to the progression of injury in ischemic border regions after 90 mins of transient focal ischemia in the cat. At the doses chosen, there appear to be no major differences in therapeutic efficacy for competitive and noncompetitive NMDA receptor antagonists.

Topics: Amino Acids; Animals; Brain; Brain Damage, Chronic; Cats; Cerebrovascular Circulation; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Ischemic Attack, Transient; Male; Neuroprotective Agents; Pipecolic Acids; Prospective Studies; Receptors, N-Methyl-D-Aspartate

Hyperhomocysteinemia has been recognized as an independent risk factor for cerebral, coronary, and peripheral atherosclerosis. To examine the contribution of homocysteine (H[cys]) in the pathogenesis of vascular diseases, we sought to determine whether the H[cys] effect on vascular smooth muscle (VSMC) proliferation is mediated by a specific receptor/transporter or is due to an interaction with growth factors or cytokines. We show that H[cys] induced c-fos and c-myb and increased DNA synthesis and cell proliferation 12-fold in neural crest-derived VSMC (N-VSMC). The H[cys] effect on N-VSMC proliferation is inhibited by Mk-801, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a glutamate-gated calcium ion channel receptor, and CGS 19755, a competitive antagonist of NMDA-type glutamate receptor. H[cys] stimulates the synthesis of mass amounts of sn-1,2 diacylglycerol, and activates protein kinase C translocation from the nucleus and cytoplasm to cell membranes. Furthermore, protein kinase C inhibitors block the growth effect mediated by H[cys]. These findings indicate that H[cys]-mediated responses are coupled to diacylglycerol-dependent protein kinase C activation. Our results suggest that homocysteine activates a receptor/transporter-like factor in neural crest derived smooth muscle.

Topics: Aorta, Abdominal; Aorta, Thoracic; Cardiovascular Diseases; Cell Division; Diglycerides; Dizocilpine Maleate; DNA; Enzyme Activation; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Genes, fos; Glutamic Acid; Homocysteine; Humans; Immunoblotting; Muscle, Smooth, Vascular; N-Methylaspartate; Oncogenes; Pipecolic Acids; Polymerase Chain Reaction; Precipitin Tests; Protein Kinase C; Receptors, N-Methyl-D-Aspartate; RNA

The effects of the N-methyl-D-aspartate (NMDA) receptor antagonists CGS19755 and MK801 and the 2-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor antagonist YM90K on spatial working memory were investigated by using a delay-interposed radial-arm maze (RAM) task in rats. CGS19755 and MK801, at the largest dose that had no effect on the performance in the nondelayed RAM task, significantly decreased the initial correct response after the 5-min delay in the delay-interposed RAM task. In contrast, YM90K had no effect on the initial correct response and arm reentries in both the delay-interposed and nondelayed RAM task. CGS19755, MK801 and YM90K, at all doses tested, did not alter the running time in either the delayed or the nondelayed RAM tasks. These results suggest that spatial working memory can be impaired by a blockade of NMDA receptor function and that such impairment is particularly sensitive to delay interposition. The lack of effect of the AMPA receptor antagonist provides additional evidence of the importance of the NMDA subtype of the glutamate receptors in cognitive processes.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Maze Learning; Memory, Short-Term; Pipecolic Acids; Psychomotor Performance; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Space Perception

Several amphetamine analogues are reported to increase striatal glutamate efflux in vivo, whereas other data indicate that glutamate is capable of stimulating the efflux of dopamine (DA) in the striatum via a glutamate receptor-dependent mechanism. Based on these findings, it has been proposed that the ability of glutamate receptor-blocking drugs to antagonize the effects of amphetamine may be explained by their capacity to inhibit DA release induced by glutamate. To examine this possibility further, we investigated in vivo the ability of glutamate antagonists to inhibit DA release induced by either methamphetamine (METH) or 3,4-methylenedioxymethamphetamine (MDMA). Both METH and MDMA increased DA efflux in the rat striatum and, in animals killed 1 week later, induced persistent depletions of DA and serotonin in tissue. Pretreatment with MK-801 or CGS 19755 blocked the neurotoxic effects of METH and MDMA but did not significantly alter striatal DA efflux induced by either stimulant. Infusion of 6-cyano-7-nitro-quinoxaline-2,3-dione into the striatum likewise did not alter METH-induced DA overflow, and none of the glutamatergic antagonists affected the basal release of DA when given alone. The findings suggest that the neuroprotective effects of NMDA antagonists do not involve an inhibition of DA release, nor do the data support the proposal that glutamate tonically stimulates striatal DA efflux in vivo. Whether phasic increases in glutamate content might stimulate DA release, however, remains to be determined.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Amines; Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine; Excitatory Amino Acid Antagonists; Male; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Pipecolic Acids; Rats; Rats, Sprague-Dawley

The effect of NMDA and AMPA receptor antagonists on a scopolamine-induced spatial cognitive deficit was investigated in rats using an 8-arm radial maze. The NMDA antagonists, MK801 and CGS19755, robustly augmented scopolamine-induced deficits but had no effect on spatial cognition when administered alone. In contrast, augmentation of the scopolamine-induced deficits was not observed when the selective AMPA antagonist, YM90K, was administered with scopolamine. These results suggest that the NMDA but not AMPA subtypes of the ionotropic glutamate receptors play important roles in regulation of the central cholinergic function related to the spatial learning and memory processes.

Topics: Animals; Cognition Disorders; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Male; Maze Learning; Pipecolic Acids; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Scopolamine

A chronic allodynia-like response to mechanical stimulation was observed in rats after severe spinal cord ischemia. This allodynia-like response was not relieved by most conventional analgesics used for treating chronic neuropathic pain. The present experiments evaluated the effects of systemically administered excitatory amino acid receptor antagonists, including the non-competitive N-methyl-D-aspartate (NMDA) receptor/channel blockers MK-801 and dextromethorphan, the competitive NMDA receptor antagonist CGS 19755 and a competitive antagonist of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor NBQX, on the chronic allodynia-like response in spinally injured rats. Systemic MK-801, dextromethorphan and CGS 19755 dose-dependently relieved the mechanical allodynia-like response. Systemic MK-801 and CGS 19755, but not dextromethorphan, also induced severe motor impairment at analgesic doses. All three NMDA antagonists increased spontaneous motor activity. Systemic NBQX reduced muscle tone and caused sedation. The mechanical allodynia was only relieved by NBQX at a sedative dose. It is concluded that systemic NMDA, but not AMPA, receptor antagonists may have an analgesic effect upon the chronic allodynia-like response. However, the analgesic effect of all NMDA antagonists was associated with side effects. Dextromethorphan, which is clinically tolerated and produced less side effects, may be useful for treating chronic pain associated with central nervous system injury.

Topics: Animals; Behavior, Animal; Chronic Disease; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Hyperalgesia; Ischemia; Motor Activity; Pipecolic Acids; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Regional Blood Flow; Spinal Cord; Spinal Cord Injuries

We tested the hypothesis that cerebrocortical blood flow and O2 consumption would be proportional to an up-regulated number of functional N-methyl-D-aspartate (NMDA) receptors. Previous work had shown a relationship between cerebral metabolism and NMDA receptor activity. We increased the specific binding to NMDA receptors in the cerebral cortex, from 2.2 +/- 0.9 to 4.5 +/- 0.8 (density units) in male Long-Evans rats by daily giving two intraperiotoneal injections (30 mg/kg) of CGS-19755, an NMDA receptor inhibitor, for 7 consecutive days (discontinued for 20 h before experiment). Twelve up-regulated (CGS treated) and 12 control rats were used in this study. Under isoflurane anesthesia and after topical stimulation of the right cerebral cortex with 10(-2) M NMDA, the blood flow (14C-iodoantipyrine method) increased from 98 +/- 11 ml/min/100 g in the unstimulated cortex of the control rats to 161 +/- 37 ml/min/100 g in the stimulated cortex. The unstimulated value for blood flow (95 +/- 7 ml/min/100 g) did not change in the upregulated group but it doubled (194 +/- 69 ml/min/100 g) in the stimulated, upregulated cortex. Similarly, O2 consumption (cryomicrospectrophotometrically determined) in normal rats increased 46%, from 9.3 +/- 1 ml/min/100 g to 13.6 +/- 4 after NMDA stimulation. While in the upregulated animals, O2 consumption increased 103% from 7.9 +/- 0.6 to 16 +/- 6.5 after NMDA stimulation. In conclusion, NMDA receptor upregulation does not alter basal cerebrocortical blood flow or O2 consumption but in the NMDA-stimulated cortex, the blood flow and O2 consumption increase is dependent on the number of NMDA receptors present.

Topics: Animals; Brain; Cerebrovascular Circulation; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gases; Hemodynamics; Male; N-Methylaspartate; Oxygen Consumption; Pipecolic Acids; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Up-Regulation

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).

Topics: Animals; Autoradiography; Behavior, Animal; Binding, Competitive; Brain; Brain Chemistry; Cerebral Cortex; Deoxyglucose; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Extrapyramidal Tracts; Glucose; Hippocampus; Isoquinolines; Limbic System; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Tetrahydroisoquinolines

The cytotoxicity induced by the transient expression of functional N-methyl-D-aspartate (NMDA) receptors has been examined with the use of a luciferase reporter assay in Chinese hamster ovary cells. Various NMDA receptor antagonists, in a dose-dependent manner, prevented a loss of luciferase activity 24 to 48 hr post-transfection of either the NR1/NR2A or NR1/ NR2B subunit receptor configurations, likely correlating to the time required to express functionally these receptors. Both glutamate and NMDA were potently cytotoxic to transfected cells previously protected by antagonists. The novel ifenprodil analog (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP101,606-27) protected cells expressing NR1/NR2B, but not those cells expressing either NR1/NR2A or, putatively, NR1/NR2A/NR2B. Decreased cytotoxicity was observed when a mutated NR1 subunit (N616R) with reduced Ca++ permeability was used in coexpression studies with NR2A or NR2B. In contrast to our results with NR1/NR2A or NR1/NR2B, cells expressing NR1/NR2C did not perish. Our studies suggest that expression of functional NMDA receptors in non-neuronal cells leads to a form of excitotoxicity similar to that observed in mammalian neurons in vitro.

Topics: Animals; Calcium; Cell Survival; CHO Cells; Cricetinae; Dizocilpine Maleate; Kynurenic Acid; L-Lactate Dehydrogenase; Luciferases; Pipecolic Acids; Piperidines; Receptors, N-Methyl-D-Aspartate; Transfection

The interaction between morphine and three antagonists of the N-methyl-D-aspartate (NMDA) receptor. MK-801 (non-competitive channel blocker), dextromethorphan (clinically available non-competitive antagonist) and CGS19755 (competitive receptor antagonist), was examined in rats with the hot plate test. The NMDA antagonists were administered intraperitoneally and none of them caused antinociception at doses that did not produce motor deficits (0.1 mg kg-1 MK-801, 30 mg kg-1 dextromethorphan and 5 mg kg-1 CGS19755). However, pretreatment with the NMDA antagonists at these doses 30 min prior to subcutaneous injection of 5 mg kg-1 morphine significantly potentiated the antinociceptive effect of morphine, with strongest effect observed with dextromethorphan. It is suggested that blockade of NMDA receptors enhances the antinociceptive effect of morphine and NMDA antagonists may improve the analgesic efficacy of morphine in the clinic.

Topics: Analgesics; Animals; Dextromethorphan; Dizocilpine Maleate; Drug Synergism; Male; Morphine; Nociceptors; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Exposure of rat hippocampal slices to 12-min hypoxia produced only mild neuronal damage, as 72% of all slices recovered their CA1-evoked population spike following a 30-min recovery period. However, when this hypoxic insult was administered in the presence of 2.5 microM kainate or AMPA, only 6 and 15% of the slices, respectively, recovered their neuronal function. This enhancement of hypoxic damage by kainate could be attenuated in a dose-dependent fashion by the kainate/AMPA antagonist GYKI 52466 but not by the competitive NMDA antagonist APV. Unexpectedly, the noncompetitive NMDA antagonist MK-801 also attenuated the kainate- and AMPA-enhanced hypoxic neuronal damage and was more efficacious than GYKI 52466. Considering (1) the ability of MK-801 to antagonize hypoxic neuronal damage in the absence or the presence of NMDA, kainate or AMPA; (2) the antihypoxic effect of MK-801 in the presence of APV + 7-chlorokynurenate, a pairing that supposedly blocks MK-801 binding to the NMDA receptor; (3) the ability of MK-801 to protect hippocampal slices against brain damage induced by depolarization + excitotoxin (50 mM KCl + mM glutamate for 60 min); and (4) the ability of diltiazem, an L-type calcium channel blocker, to protect hippocampal slices against hypoxic neuronal damage, we conclude that the mode of action of MK-801 cannot be explained by its NMDA receptor antagonistic properties alone. A possible blockade of Ca2+ channels, most likely of the L-type, by MK-801 should be considered along with other mechanisms.

Topics: 2-Amino-5-phosphonovalerate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Anti-Anxiety Agents; Benzodiazepines; Diltiazem; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Hypoxia, Brain; In Vitro Techniques; Kynurenic Acid; Membrane Potentials; Neurons; Nifedipine; Pipecolic Acids; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate

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)

Topics: Animals; Body Temperature; Brain Chemistry; Dizocilpine Maleate; Hydroxyindoleacetic Acid; Male; N-Methyl-3,4-methylenedioxyamphetamine; Pipecolic Acids; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Serotonin

Ethanol, acutely, is a potent inhibitor of the function of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. After chronic exposure of animals to ethanol, however, the NMDA receptor in brain is upregulated. This upregulation is associated with the occurrence of ethanol withdrawal seizures. When cultured cerebellar granule neurons are exposed chronically to ethanol, the resulting upregulation of NMDA receptor function renders the cells more susceptible to glutamate-induced neurotoxicity. The present studies show that chronic ethanol exposure produces an increase in NMDA receptor number in the cells, measured by ligand binding to intact cells. Glutamate-induced excitotoxicity, both in control and ethanol-exposed cells, is blocked by the same NMDA receptor antagonists previously shown to block ethanol withdrawal seizures in animals. In addition, glutamate neurotoxicity is blocked by acute (2-hr) pretreatment of cells with ganglioside GM1 or by chronic (3 days) treatment with the ganglioside. Acute ganglioside treatment does not interfere with the initial rise in intracellular calcium caused by glutamate, whereas this response is downregulated after chronic ganglioside treatment. These results suggest that therapeutic agents can be developed to block both ethanol withdrawal signs and the neuronal damage that accompanies ethanol withdrawal. Furthermore, chronic ganglioside treatment during ethanol exposure has the potential to prevent changes in the NMDA receptor that lead to withdrawal seizures and enhanced susceptibility to excitotoxicity.

Topics: Alcohol Withdrawal Delirium; Alcoholism; Animals; Animals, Newborn; Cells, Cultured; Cerebellum; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; G(M1) Ganglioside; Glutamic Acid; Kynurenic Acid; Neurons; Pipecolic Acids; Rats; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Up-Regulation

Several studies have indicated important functional interactions between volatile anesthetics and the N-methyl-D-aspartate (NMDA) class of glutamate receptors. In the present study, we examined the effects of diethyl ether, chloroform, methoxyflurane, halothane, enflurane, and isoflurane on (1) glutamate activation of the NMDA receptor complex, including glycine reversal of anesthetic action, as revealed by [3H]-(5R, 10S)-(+)methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine, dizocilpine (MK-801) binding to the cation channel, and (2) [3H]cis-4-( phosphonomethyl)piperidine-2-carboxylic acid (CGS 19755) binding to the glutamate recognition site of the NMDA receptor In agreement with previous studies, glutamate increased the binding of 1 nM [3H]MK-801, measured after a 1-hr incubation at 37 degrees, by up to several hundred fold. This stimulation was blocked by glutamate antagonists and potentiated by glycine with an EC50 of approximately 0.03 muM. Glycine also had a direct stimulatory effect on [3H]MK-801 binding at much higher concentrations ( > or = 10 muM). All of the anesthetics examined depressed glutamate stimulation of [3H]MK-801 binding in a concentration-dependent manner with the following order of potency: halothane > or = enflurane > methoxyflurane > chloroform > diethyl ether. This inhibition of [3H]MK-801 binding was observed at concentrations that are routinely attained in the cerebrospinal fluid during surgical anesthesia. Moreover, the inhibition was reversed rapidly following removal of the anesthetics from the assay medium. Inclusion of glycine in the incubation medium markedly attenuated anesthetic-induced inhibition of glutamate-sensitive [3H]MK-801 binding with an EC50 of between 0.1 and 1 muM. Thus, this reversal by glycine correlated with its potentiating as opposed to its direct stimulatory, effect on NMDA receptors. Anesthetic inhibition of [3H]MK-801 binding could not be overcome by raising the glutamate concentration (i.e. the interaction did not appear to be competitive with respect to glutamate) unless glycine was present. Binding of [3H]CGS 19755 to the glutamate recognition site was also inhibited by each of the anesthetics examined. However, with the exception of chloroform, all of the anesthetics were more potent inhibitors of glutamate-stimulated [3H]MK-801 binding than they were of [3H]CGS 19755 binding. [3H]CGS 19755 binding saturation curves in the presence of halothane and enflurane indicated a decrease in the

Topics: Anesthetics, Inhalation; Animals; Dizocilpine Maleate; Glutamic Acid; Glycine; Male; Pipecolic Acids; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

The effects of the muscarinic antagonists scopolamine HBr and MeBr, the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the N-methyl-d-aspartate (NMDA) antagonists MK-801 and CGS-19755 on performance of rats in a delayed matching-to-position task were examined. Pretreatment with scopolamine HBr (0.05 and 0.1 mg/kg), resulted in a delay-dependent decrease in the percentage of correct responses and discriminability (log d), but had no effect on either the latency to complete trials, or the rate of trial completion during the fixed duration session. Scopolamine MeBr (0.1 mg/kg) did not impair percent correct or increase the response latency but did decrease the rate of trial completion. 8-OH-DPAT (up to 0.3 mg/kg), had no effect on percent correct, but did induce a small decrease in discriminability. The impairment in discriminability occurred only at a dose that substantially reduced the rate of trial completion. Both MK-801 (0.05 mg/kg) and CGS 19755 (10 mg/kg) induced a delay-independent impairment in percent correct, discriminability and a reduction in the rate of trial completion without affecting latency. A lower dose of CGS 19755 (5.0 mg/kg) induced a slight impairment in discriminability without significantly affecting the other measures. Taken together, these results demonstrate some dissociation between drug-induced cognitive and motor/motivational deficits in the DMTP test. However, the data question the specificity of putative cognitive impairments reported in many previous studies with the 5-HT1A agonist 8-OH-DPAT.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Cognition; Conditioning, Operant; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Motor Activity; Muscarinic Antagonists; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Scopolamine; Scopolamine Derivatives; Serotonin Receptor Agonists

The N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors are involved in the electrical and behavioural generalization of epileptiform activity within the brain. In rats, both competitive and non-competitive NMDA antagonists induce three dose-dependent stages of EEG patterns: 1) increase in cortical desynchronization periods; 2) increase in amplitude of cortical high frequency (20-30 Hz), low voltage (30-50 microV) background activity; 3) appearance of cortical slow (2-3 Hz) wave-sharp wave complexes. These EEG changes are accompanied by stimulatory-depressive behavioural effects such as stereotypy (circling, head weaving) and ataxia. In the present study, the influence of the prototypic anticonvulsant diphenylhydantoin (DPH) has been tested on the EEG and behavioural effects induced by the non-competitive NMDA antagonists phencyclidine (PCP) and dizocilpine (MK-801) and by the competitive NMDA antagonist cis-4-phosphonomethyl-2-piperidine-carboxylic acid (CGS 19755). Even though DPH (up to 100 mg/kg IP) did not markedly affect basal cortical EEG activity, at doses of 10-100 mg/kg IP it potentiated all the EEG effects induced by the NMDA antagonists. These data support involvement of NMDA neurotransmission in the pharmacological effects of DPH.

Topics: Animals; Behavior, Animal; Cortical Synchronization; Dizocilpine Maleate; Drug Synergism; Electroencephalography; Male; N-Methylaspartate; Phencyclidine; Phenytoin; Pipecolic Acids; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior

Focal cerebral ischemia was induced in rats by permanent occlusion of the left middle cerebral artery (MCA). The cerebroprotective properties of the competitive NMDA antagonist CGP 40116 were evaluated in that model and compared to the neuroprotective effects of MK 801, D-CPPene and CGS 19755 under the same experimental conditions. Infarct volume was assessed using in vivo magnetic resonance imaging. The rank order of potency for the NMDA antagonists tested was MK 801 > CGP 40116 approximately D-CPPene > CGS 19755. CGP 40116 dose-dependently reduced the volume of cortical infarction, with an ED50 of 11 mg/kg i.v., and its cerebroprotective efficacy was comparable to that of MK 801. Neuroprotection by CGP 40116 was still apparent when treatment was started 30 minutes after MCA occlusion. It is concluded that CGP 40116 is an effective cerebroprotectant with potential clinical utility for amelioration of focal cerebral ischemic damage.

Topics: 2-Amino-5-phosphonovalerate; Animals; Blood Pressure; Brain Ischemia; Dizocilpine Maleate; Dose-Response Relationship, Drug; Magnetic Resonance Imaging; Male; Neuroprotective Agents; Pipecolic Acids; Piperazines; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate

The object of this investigation was to determine whether glutamate uptake affects the apparent potency of the competitive antagonists DL-2-amino-5-phosphonovalerate and CGS-19755 in blocking NMDA receptor-mediated neurotoxicity. In astrocyte-rich rat cortical cultures we observed that DL-2-amino-5-phosphonovalerate and CGS-19755 were 24 and 16 times more potent against NMDA than against glutamate-induced toxicity. In contrast, DL-2-amino-5-phosphonovalerate was equipotent against the two agonists in astrocyte-poor cultures, in which dendrites are directly exposed to the extracellular medium. With the noncompetitive NMDA antagonist MK-801, similar potencies were observed against glutamate (212 +/- 16 nM) and against NMDA (155 +/- 9 nM) neurotoxicity. These results may be explained if we assume that the neuronal cell body is less susceptible than the dendrites to NMDA receptor-mediated toxicity, and that the action of glutamate in astrocyte-rich cultures is confined to the cell body. In this case, one would expect that higher concentrations of glutamate would be needed to produce toxicity in astrocyte-rich cultures, and that higher concentrations of competitive antagonists would be needed to overcome this toxicity. Our observations help explain the pharmacology of the competitive NMDA antagonists against NMDA receptor-mediated neurotoxicity but also suggest the possibility that, because the cell body and dendrites may be distinct sites for neurotoxicity, they might also involve different mechanisms of toxicity.

Topics: 2-Amino-5-phosphonovalerate; Animals; Astrocytes; Binding, Competitive; Cell Survival; Cells, Cultured; Cerebral Cortex; Dendrites; Dizocilpine Maleate; Embryo, Mammalian; Glutamates; Glutamic Acid; N-Methylaspartate; Neurons; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

The effects of the selective non-competitive NMDA receptor antagonist dizocilpine (MK801) and the competitive NMDA receptor antagonist CGS19755 upon local blood flow (lCBF) and local glucose utilisation (lCGU) were examined in 81 neuroanatomically discrete regions of the conscious rat brain using the [14C]iodoantipyrine and [14C]2-deoxyglucose quantitative autoradiographic techniques, respectively. Animals received dizocilpine (0.3 mg/kg), CGS19755 (30 mg/kg) or saline vehicle (2 ml/kg) 10 min prior to the initiation of lCGU studies while blood flow determinations were performed in parallel groups of animals 20 min after drug administration. Dizocilpine significantly increased lCGU in 33 of the 81 regions measured (most notably in cortical and subcortical limbic structures and in the basal ganglia) while reducing glucose use in seven brain areas (frontoparietal and somatosensory cortex, and in areas subserving auditory function). In contrast, CGS19755 significantly reduced lCGU use in 39 of the 81 areas examined while increases were observed in only three areas (anterior piriform cortex, substantia nigra pars reticulata, and posterior thalamic nucleus). Following Dizocilpine administration, there was evidence of widespread (64 of the 81 areas studied) increases in lCBF, while blood flow was reduced in the inferior colliculus. Significant increases in lCBF were also noted in 26 brain areas of CGS19755-treated rats while in one area (flocculus) blood flow was reduced. In saline-treated rats there was a close correlation between lCBF and lCGU. Dizocilpine administration was associated with an increase in the overall lCBF:lCGU ratio from 1.56 ml/mumol (in saline-treated rats) to 2.34 ml/mumol. In some brain areas (CA1 subfield of the dorsal hippocampus, somatosensory cortex and nucleus accumbens) there was evidence of focal disturbances in flow-metabolism relationship. While a similar increase in the overall lCBF-lCGU use ratio was evident in CGS19755 treated animals, there was no evidence of focal uncoupling of the flow metabolism relationship in any of the 81 brain areas examined. These data show that whilst both competitive and non-competitive NMDA receptor antagonists increased cerebral tissue perfusion beyond that required to meet underlying metabolic demand, focal disturbances in the flow metabolism relationship were observed only in dizocilpine-treated rats.

Topics: Animals; Brain; Cerebrovascular Circulation; Dizocilpine Maleate; Glucose; Male; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Glutamate antagonists are the most powerful neuroprotective drugs in laboratory studies of focal cerebral ischemia. Because the majority of clinical conditions in which focal brain ischemia occurs are associated with high intracranial pressure (ICP), we have used the rat acute subdural hematoma model to evaluate the effects of three glutamate N-methyl-D-aspartate antagonists, MK-801, CGS 19755 (SELFOTEL), D-CPP-ene, and mannitol, upon ICP and also upon the volume of ischemic brain damage. Only mannitol produced a significant reduction in ICP and improved cerebral perfusion pressure. The three glutamate antagonists did not significantly affect ICP or cerebral perfusion pressure, but they were associated with a significantly smaller zone of focal brain damage, when compared to the mannitol and saline groups. N-methyl-D-aspartate antagonists do not increase ICP or jeopardize cerebral perfusion pressure when administered under anesthesia with a controlled PaCO2 level. Further studies in humans are indicated.

Topics: Acute Disease; Animals; Disease Models, Animal; Dizocilpine Maleate; Hematoma, Subdural; Hemodynamics; Intracranial Pressure; Male; Mannitol; N-Methylaspartate; Pipecolic Acids; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Acute administration of morphine (10 mg/kg) to rats elicited an increase in locomotion that became sensitized upon repeated treatment over 14 days. Administration of the noncompetitive N-methyl-D-aspartate receptor (NMDA) antagonist MK-801 (0.1 or 0.25 mg/kg) prior to each morphine injection prevented the development of behavioral sensitization to morphine, an effect that persisted even after a 7-day withdrawal from repeated treatment. Sensitization was also prevented by coadministration of the competitive NMDA receptor antagonist CGS 19755 (10 mg/kg). In contrast, acute pretreatment with MK-801 did not alter the response of sensitized rats to morphine challenge, indicating that MK-801 does not prevent the expression of sensitization. When administered alone, MK-801 produced stereotyped movements at moderate doses (0.25 mg/kg) and horizontal locomotion at higher doses (0.5 mg/kg). Repeated administration of 0.25 mg/kg MK-801 elicited sensitization to its own locomotor stimulatory effects, such that this dose became capable of eliciting horizontal locomotion. Sensitization was not seen during repeated administration of 0.1 mg/kg MK-801 or 10 mg/kg CGS 19755, although both of these pretreatments did produce a sensitized response to subsequent challenge with 0.25 mg/kg MK-801. This effect was enhanced by coadministration of morphine, even though repeated administration of morphine alone failed to sensitize rats to MK-801 challenge. These results suggest a complex interplay between NMDA and opioid receptors, such that NMDA antagonists prevent morphine sensitization while morphine enhances the ability of NMDA antagonists to elicit sensitization to their own locomotor stimulatory effects.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Male; Morphine; Motor Activity; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Kainic acid caused a marked decrease of the electrically evoked release of [3H]dopamine from rat striatal slices 4 days after its injection (10 nmol/microliters) into the corpus striatum. This damage was prevented by the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) when co-injected with kainic acid into the striatum. Prior systemic administration of the NMDA selective antagonists (cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), dizocilpine (MK-801) and ketamine did not alter the kainate effect. Previous destruction of the cortico-striatal pathway abolished the kainate-induced decrease of [3H]dopamine release. When injected into the striatum, domoic acid or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) mimicked kainic acid and damaged the dopaminergic nigro-striatal afferents. The [3H]dopamine release evoked by electrical stimulation of slices of frontal cortex was unaffected following local injections of kainic acid. Taken together, the results indicate that AMPA/kainate receptors play a key role in the impairment of [3H]dopamine release caused by kainate in the striatum. However, the kainic acid effect is probably indirect since it appears to require the availability of endogenous glutamate originating from cortico-striatal afferents.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine; Electric Stimulation; Kainic Acid; Ketamine; Male; N-Methylaspartate; Neuromuscular Depolarizing Agents; Neurons, Afferent; Pipecolic Acids; Quinoxalines; Rats; Rats, Sprague-Dawley

Micromolar concentrations of beta-amyloid (25-35) or substance P stimulated [3H]MK-801 binding in the presence of low concentrations of glutamate (1 microM) and glycine (0.02 microM). Unlike polyamines spermine and spermidine, neither beta-amyloid (25-35) nor substance P increased [3H]MK-801 binding in the presence of maximally stimulating concentrations of glutamate and glycine. 5,7-Dichloro-kynurenic acid, CGS-19755, and arcaine completely inhibited the stimulated [3H]MK-801 binding. There was an apparent decreased potency of the [3H]MK-801 binding inhibition curve for 5,7-dichlorokynurenic acid, but not CGS-19755 or arcaine, in the presence of either beta-amyloid (25-35) or substance P. The compounds do not appear to act through the strychnine-insensitive glycine binding site because neither beta-amyloid (25-35) nor substance P displaced [3H]glycine binding. Full-length beta-amyloid (1-40), up to 10 microM, did not stimulate [3H]MK-801 binding. Concentrations > 10 microM could not be tested because they formed large aggregate precipitates in the assay. The data indicate that beta-amyloid (25-35) or substance P does not stimulate [3H]MK-801 binding at either the N-methyl-D-aspartate, glycine, or polyamine binding sites. Furthermore, the nonpeptide substance P receptor (NK1) antagonist, CP-96,345, did not block beta-amyloid (25-35)- or substance P-stimulated [3H]MK-801 binding. Therefore, the effect is not due to an interaction between the substance P receptors and the N-methyl-D-aspartate receptor-operated ionophore. Finally, if these observations can be verified using single-channel recording techniques, they may have implications in the pattern of selective neuronal loss observed in patients with neurodegenerative processes such as Alzheimer's, Parkinson's, and Huntington's diseases.

Topics: Amino Acid Sequence; Amyloid beta-Peptides; Animals; Biguanides; Cell Membrane; Cerebral Cortex; Dizocilpine Maleate; Glutamates; Glutamic Acid; Glycine; Kinetics; Molecular Sequence Data; N-Methylaspartate; Peptide Fragments; Pipecolic Acids; Rats; Receptors, N-Methyl-D-Aspartate; Sequence Homology, Amino Acid; Substance P

Injection of the N-methyl-D-aspartate receptor agonist, quinolinic acid, into the rat striatum in vivo results in the degeneration of cholinergic and GABAergic neurons, as determined seven days later using the marker enzymes, choline acetyltransferase and glutamate decarboxylase, respectively. Such damage was dose-dependently prevented by CGP 37849 or MK-801 (competitive and uncompetitive N-methyl-D-aspartate receptor antagonists, respectively) administered systemically or intrastriatally at the same time as quinolinic acid. The neuroprotective activity of CGP 37849 was associated with the D-enantiomer, CGP 40116 (ED50 7.5 mg/kg i.p.), which was approximately 1.5-fold and 3.5-fold more potent than the related compounds, D-CPPene and CGS 19755, respectively. CGP 37849 was a weaker neuroprotectant than MK-801 (ED50 0.8 mg/kg i.p) when administered systemically, but was dramatically more potent following coinjection with quinolinic acid (ED50's 0.2 and 117 nmol, respectively). When injected intrastriatally 0.5-2 h post-quinolinic acid, CGP 37849 was protective over the entire period studied, whereas MK-801 was less effective at all post-quinolinic acid injection times. The finding that CGP 37849 is neuroprotective when administered intrastriatally 1-2 h post-quinolinic acid supports the hypothesis that a period exists following excitotoxic insult in which neurons are not committed to die, and can be rescued by blockade of ongoing N-methyl-D-aspartate receptor activation. Competition studies indicated that, when coinjected with 100-400 nmol quinolinic acid into the striatum, CGP 37849 exhibited kinetics predicted of a competitive N-methyl-D-aspartate receptor antagonist (declining neuroprotective potency with increasing doses of agonist), whereas MK-801 displayed a complex picture, with weak protective activity at low doses of quinolinic acid. Following systemic administration, neither antagonist was markedly affected by the dose of excitotoxin. When given i.p. at up to 6 h post-quinolinic acid, CGP 37849 and MK-801 showed essentially identical profiles of post-insult protection; degeneration of cholinergic neurons was reduced significantly throughout the entire post-insult period, whereas GABAergic neurons were protected only when drugs were administered 2 h or earlier post-quinolinic acid. The data indicate that competitive and uncompetitive N-methyl-D-aspartate receptor antagonists are effective neuroprotectants in vivo, and that parameters such as drug li

Topics: 2-Amino-5-phosphonovalerate; Acetylcholine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Binding, Competitive; Biomarkers; Cell Death; Choline O-Acetyltransferase; Corpus Striatum; Dizocilpine Maleate; Drug Administration Schedule; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Injections; Injections, Intraperitoneal; Kainic Acid; Male; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Neurotoxins; Pipecolic Acids; Piperazines; Quinolinic Acid; Rats; Receptors, N-Methyl-D-Aspartate

Human immunodeficiency virus (HIV-1) infection often results in central nervous system (CNS) dysfunction, yet the mechanism(s) of action for HIV-1 in the CNS are not fully understood. In the present study gp120, the HIV-1 envelope glycoprotein, was shown to selectively inhibit N-methyl-D-aspartate (NMDA) receptor function. In addition to inhibiting radioligand binding to rat NMDA receptors, gp120 inhibited NMDA-induced currents in Xenopus oocytes, attenuated NMDA-stimulated calcium flux and cytotoxicity in cultured cerebellar granule cells, and provided partial protection against NMDA-induced lethality in vivo. These findings suggest that NMDA receptor complex is a possible site of action of HIV-1 within the CNS.

Topics: Animals; Calcium Channel Blockers; Cells, Cultured; Dizocilpine Maleate; Electrophysiology; HIV Envelope Protein gp120; N-Methylaspartate; Oocytes; Phencyclidine; Pipecolic Acids; Radioligand Assay; Rats; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Xenopus

Behavioral activation following systemic administration of the N-methyl-D-aspartic acid receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d) cyclohepten-5,10-imine; dizocilpine] was examined in unlesioned control and in neonatal-6-hydroxydopamine (OHDA) lesioned rats. Neonatal-6-OHDA lesioned animals were found more sensitive than control rats and female rats more sensitive than males to this MK-801-induced behavioral activation. CGS-19755, a competitive NMDA antagonist, also increased activity in neonatally lesioned animals. The increased activity level following MK-801 administration to neonatally lesioned rats was reduced, but not eliminated, by pretreatment with alpha-methyltyrosine, indicating that endogenous catecholamines were partially responsible for this action of MK-801. Furthermore, neither a D1- nor a D2-dopamine antagonist was totally effective alone in reducing MK-801-induced behavioral activation in the neonatally lesioned rats, but MK-801-induced activity was reduced to the level observed after alpha-methyltyrosine when both dopamine antagonists were administered in combination. In contrast to these results, alpha-methyltyrosine virtually eliminated the MK-801-induced activity in adult-lesioned rats. When individual behaviors induced by MK-801 were examined in neonatal-6-OHDA lesioned rats, MK-801 did not produce the same behaviors as L-dihydroxyphenylalanine or a D1- or D2-dopamine agonist. Whereas MK-801 had no major effect on most behaviors induced by specific D1- or D2-dopamine agonists, it blocked some behaviors produced after L-dihydroxyphenylalanine administration, including the self-injurious behavior. Repeated MK-801 treatment resulted in increasingly greater motor activity, but this was not related to increased D1-dopamine receptor sensitization. In support of a regional action of MK-801, MK-801 induced c-fos-like immunoreactivity in the cerebral cortex, but not in the nucleus accumbens or striatum. The action of MK-801 to increase c-fos-like immunoreactivity in cerebral cortex was reduced, but not blocked, by SCH-23390. Additionally, MK-801 reduced, but did not eliminate, D1-dopamine agonist induced c-fos-like immunoreactivity in striatum. These data suggest that MK-801 not only can facilitate dopamine release within specific brain regions, but has behavioral and functional actions distinct from dopamine agonists.

Topics: alpha-Methyltyrosine; Animals; Animals, Newborn; Behavior, Animal; Brain; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Female; Gene Expression; Genes, fos; Levodopa; Male; Methyltyrosines; N-Methylaspartate; Pipecolic Acids; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Serotonin; Tyrosine 3-Monooxygenase

N-methyl-D-aspartate (NMDA) receptor antagonists, which block one of the glutamate receptors, have provided evidence of cerebral protection in animal models of focal cerebral ischemia. We examined the effect of neuroprotective doses of one noncompetitive (dizocilpine) and two competitive (D-CPP-ene, CGS 19755) NMDA antagonists on the minimum alveolar anesthetic concentration (MAC) of isoflurane in rats. A single bolus injection of any of the three NMDA antagonists produced a significant (P < 0.01) and sustained (> 3 h) decrease in the MAC of isoflurane. Dizocilpine decreased MAC by 33%-38% at a dose of 0.15 mg/kg and 48%-54% at a dose of 0.5 mg/kg. D-CPP-ene decreased MAC by 32%-37% at a dose of 1.5 mg/kg and 39%-45% at a dose of 4.5 mg/kg. CGS 19755 decreased MAC by 19%-24% at a dose of 3 mg/kg and 49%-58% at a dose of 10 mg/kg. Dizocilpine, but not the competitive antagonists, produced a small transient decrease in mean arterial blood pressure. The sustained anesthetic potency of neuroprotective doses of NMDA antagonists supports the idea that glutaminergic receptor activity is involved in determining the anesthetic state.

Topics: Anesthesia, Inhalation; Animals; Dizocilpine Maleate; Isoflurane; Male; Pipecolic Acids; Piperazines; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

We have previously reported that the response latency in the mouse hot-plate test is affected differently by spinal intrathecal (i.t.) injection of competitive and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, in that only the former produces an antinociceptive effect. Since the lipophilic non-competitive antagonists will redistribute rapidly from the spinal injection site, it is conceivable that they reach sites where they counteract the spinal antinociceptive effect. In the present study, we have tested this hypothesis by comparing the antinociceptive effect of the competitive NMDA receptor antagonist CGS 19755 and the non-competitive NMDA receptor antagonist MK-801 after i.t., intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration as well as after combinations thereof. CGS 19755 injected i.p. or i.c.v. and MK-801 injected i.p. or i.t. attenuated the antinociceptive effect of i.t. injected CGS 19755. Both i.p. and i.c.v. administration of either CGS 19755 or MK-801 dose-dependently impaired motor function without producing antinociceptive effects. Thus, the effect of CGS 19755 and MK-801 on the motor system was found to be separate from their antinociceptive effect. In a separate experiment, changes in hind-paw skin temperature were excluded as a possible confounding factor. These findings demonstrate that supraspinal systems can limit the spinal antinociceptive effect of NMDA receptor antagonists.

Topics: Animals; Cerebral Ventricles; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hot Temperature; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Spinal; Mice; Mice, Inbred Strains; N-Methylaspartate; Pain; Pipecolic Acids; Receptors, N-Methyl-D-Aspartate; Skin Temperature; Spinal Cord; Time Factors

The acute effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine [(+)-MK-801] on 1) dopamine depletion caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 2) the biodisposition of the MPTP metabolite 1-methyl-4-phenylpyridinium (MPP+) and 3) MPTP-induced ATP loss were investigated in the mouse striatum. Systemic administration of a single dose of MPTP (40 mg/kg s.c.) to C57BL/6 mice rapidly decreased striatal dopamine levels to 30% of control values. A single injection of (+)-MK-801 (1 mg/kg i.p.) 30 min before MPTP treatment completely prevented striatal dopamine depletion at 1.5 and 4 hr. The competitive NMDA antagonist CGS-19755 also completely protected against MPTP-induced acute dopamine depletion at 4 hr in the striatum. The action of (+)-MK-801 was only temporary, however, because at 12 hr, the degree of dopamine depletion was not different between the (+)-MK-801/MPTP-treated animals and mice treated with MPTP alone. Repeated injections of (+)-MK-801 at 4-hr intervals did not provide any additional protective effect. (+)-MK-801 administration before MPTP exposure did not appear to affect the production of MPP+, but it did significantly delay its elimination from the striatum. There was a significant correlation between levels of dopamine and MPP+ both in the presence and in the absence of (+)-MK-801. Finally, MPTP-induced striatal ATP loss was not affected by pretreatment with (+)-MK-801.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; Adenosine Triphosphate; Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine; Drug Interactions; Male; Mice; Mice, Inbred C57BL; N-Methylaspartate; Pipecolic Acids; Time Factors

The tissue distribution of [3H]cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) and [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (NK-801) was investigated after a single IT injection into lumbar spinal cord of mice. The level of radioactivity was analyzed in the lumbar, thoracic, and cervical spinal cord, brainstem, frontal cortex, liver, lungs, kidneys, stomach, intestine, spleen, heart, and blood from 5 min up to 6 h after injection. Within the CNS, [3H]CGS 19755 redistributed slowly from the site of injection toward the brainstem and cortex, peaking in the cortex 3-4 h after IT injection. At no time, however, did the relative level per gram of tissue in the frontal cortex exceed 10% of the relative level in the lumbar region of the spinal cord. The highest peripheral level of [3H]CGS 19755 was found in the kidneys. [3H]MK-801 redistributed rapidly from the spinal cord injection site to the peripheral organs. The highest peripheral levels of [3H]MK-801 were found in the lungs and liver, where the radioactivity peaked at 10 and 30-60 min, respectively, after injection. The relative levels of [3H]CGS 19755 were consistently higher in CNS tissues (except for the first 15 min in the frontal cortex) and blood than the corresponding levels of [3H]MK-801. The opposite relationship was true in the liver, lungs, kidneys, stomach, intestine, spleen, and heart. The effect on the response latency in the hot-plate test was quantified in the same animals immediately prior to sacrifice for the distribution study.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Dizocilpine Maleate; Injections, Spinal; Male; Mice; N-Methylaspartate; Pain Measurement; Pipecolic Acids; Reaction Time; Receptors, N-Methyl-D-Aspartate; Tissue Distribution

Extracellular single-unit recordings were used to assess the effects of PCP and PCP-like drugs (MK-801 and TCP) on the burst firing of ventral tegmental A10 dopamine neurons in the rat. The effects of these noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were compared to the potent and competitive NMDA antagonists CGS 19755 and (+/-)CPP, and to BTCP, a PCP-derivative possessing little affinity for the PCP binding site within the ion channel gated by NMDA. PCP, MK-801, and TCP produced dose-dependent increases in the firing rate, which were accompanied by increases in the amount of burst activity, the number of action potentials within a burst, and the conversion of nonbursty cells to bursty. However, the coefficient of variation, a measure of the regularity of firing, was not significantly altered. These predominately excitatory effects contrast with the inhibition of firing, decrease in bursting, and regularization of pattern produced by BTCP. CGS 197555 and (+/-)CPP failed to alter any of the measured parameters. Thus, the increase in firing rate and amount of burst activity of dopamine neurons produced by PCP and PCP-like drugs, and the resultant hyperdopaminergia within the mesolimbic-mesocortical regions, could underlie the psychotomimetic properties of these compounds. Moreover, this effect would not appear to be related to a loss of activity at the NMDA recognition site, as evidenced by the lack of effect of the competitive NMDA antagonists.

Topics: Action Potentials; Animals; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Illicit Drugs; Male; N-Methylaspartate; Neurons; Phencyclidine; Pipecolic Acids; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Stereotaxic Techniques; Tegmentum Mesencephali; Vibrissae

The ethanol-like discriminative stimulus effects of N-methyl-D-aspartate (NMDA) antagonists that act at the NMDA recognition site [(D)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CPPene) and cis-4-phosphonomethyl-2-piperidine carboxylic acid] or within the NMDA associated cation channel [phencyclidine (PCP) and dizocilpine] were evaluated in rats trained to discriminate ethanol or PCP from vehicle in a two-lever discrimination procedure. Three groups of rats were trained to discriminate 1.0, 1.5 or 2.0 g/kg of ethanol from water and one group was trained to discriminate 1.5 mg/kg of PCP from saline. In the ethanol-trained groups, both PCP (1.0-5.6 mg/kg; i.p.) and dizocilpine (0.03-0.3 mg/kg; i.p.) completely substituted for ethanol in every rat tested, although the dizocilpine resulted in only partial substitution in rats trained to discriminate 1.0 g/kg of ethanol. As the training dose of ethanol increased, the potency of PCP and dizocilpine to substitute for ethanol increased. In contrast, CPPene (1-17 mg/kg; i.p.) and cis-4-phosphonomethyl-2-piperidine carboxylic acid (5.6-17 mg/kg; i.p.) resulted in partial substitution for ethanol, with lower amounts of ethanol-appropriate responding as the training dose of ethanol increased. These data indicate that uncompetitive antagonism of NMDA neurotransmission at sites within the cation channel produce discriminative stimulus effects that are similar to those of ethanol, particularly to higher ethanol doses. Neither ethanol (0.5-1.5 g/kg; i.p.) nor CPPene (5.6 and 10 mg/kg) completely substituted for the discriminative effects of PCP. The asymmetrical generalizations between ethanol and PCP are discussed in terms of the mixed discriminative effects of ethanol.

Topics: Animals; Discrimination Learning; Dizocilpine Maleate; Ethanol; Generalization, Psychological; Male; Phencyclidine; Pipecolic Acids; Piperazines; Rats; Receptors, N-Methyl-D-Aspartate

The purpose of the present study was to examine the effects of N-methyl-D-aspartate (NMDA) receptor blockade on the activity of tuberoinfundibular dopaminergic (TIDA) neurons in male and female rats. TIDA neuronal activity was estimated by measuring either the accumulation of 3,4-dihydroxyphenylalanine (DOPA) 30 min after the administration of the decarboxylase inhibitor NSD-1015 or the concentration of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence. The non-competitive NMDA receptor antagonist MK-801 markedly reduced prolactin secretion in both male and female rats. MK-801 also produced a dose- and time-dependent decrease in the activity of TIDA neurons in female rats, but had no effect on the activity of TIDA neurons in either intact, orchidectomized or orchidectomized, testosterone-treated male rats. Removal of the tonic stimulatory effects of prolactin on TIDA neurons in female rats by immunoneutralization of endogenous prolactin failed to alter the responsiveness of TIDA neurons to the inhibitory effects of MK-801. On the other hand, MK-801 was unable to inhibit TIDA neurons in ovariectomized female rats, but the responsiveness of TIDA neurons to MK-801 in ovariectomized female rats was restored following estrogen replacement, even in the absence of prolactin. Like MK-801, the competitive NMDA receptor antagonist CGS-19755 produced a dose-dependent decrease in TIDA neuronal activity in female rats, which was prevented in a dose-dependent manner by the NMDA receptor agonist D,L-(tetrazol-5-yl) glycine. Taken together, these results reveal a sexual difference in the responsiveness of TIDA neurons to NMDA receptor antagonists, and suggest that estrogen positively modulates NMDA receptor-mediated, tonic stimulation of TIDA neurons in female rats by a prolactin-independent mechanism.

Topics: Animals; Dizocilpine Maleate; Dopamine; Female; Glycine; Hypothalamus, Middle; Male; Neurons; Pipecolic Acids; Prolactin; Rats; Receptors, N-Methyl-D-Aspartate; Sex Characteristics; Tetrazoles

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

Antagonists of 4 distinct regulatory sites on the N-methyl-D-aspartate (NMDA) receptor were tested for their ability to attenuate NMDA-mediated acute excitotoxicity in isolated chick retina of various embryonic ages between days 11 and 19 in ovo. Acute excitotoxicity was monitored by histology and by release of endogenous gamma-aminobutyric acid (GABA) into the medium during 30 min of incubation with 50 microM NMDA. The uncompetitive PCP channel site antagonist, MK-801, the competitive antagonist, CGS 19755, and the strychnine-insensitive glycine site antagonist, 7-chlorokynurenate, completely blocked NMDA-induced cell swelling and increased GABA release at all ages tested. Potencies versus NMDA were MK-801 greater than CGS 19755 greater than 7-chlorokynurenate with IC50S of 0.02, 0.62, and 15 microM, respectively. NMDA antagonism by the polyamine site antagonist, ifenprodil, differed from other classes of antagonists in several respects. At the earlier embryonic ages tested (E12-13) ifenprodil provided differential protection; completely blocking somal and neuritic swelling in most but not all inner nuclear layer neurons and inner plexiform processes. In dose-response studies, ifenprodil attenuated the NMDA-induced increase in medium GABA at all ages tested with an Imax of 10 microM. Ifenprodil, however, showed a decreased ability to completely protect some NMDA-sensitive neurons. This was reflected both histologically and by GABA release. Maximal attenuation of NMDA evoked GABA release was 83, 80, 62 and 50% at days E12, 13, 15 and 19, respectively. Histologically, differential protection was seen at E12 and 13, in limited areas at E15, and was no longer present at E19.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acids; Animals; Biogenic Polyamines; Chick Embryo; Dizocilpine Maleate; Kynurenic Acid; N-Methylaspartate; Pipecolic Acids; Piperidines; Receptors, Glutamate; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine; Retina

Topics: Amygdala; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electric Stimulation; Hippocampus; Kindling, Neurologic; Kynurenic Acid; Male; Neural Pathways; Pipecolic Acids; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Synapses; Synaptic Transmission

The density of N-methyl-D-aspartate (NMDA) receptors on membranes prepared from cultured cortical neurons was determined using binding assays with [125I]I-MK-801 after exposure of cultures to antagonists of the NMDA receptor complex. The density of binding sites for [125I]I-MK-801 was increased by 40-80% after exposure to D-2-amino-5-phosphonopentanoic acid (D-AP5), with no change in the number or viability of neurons. The effect of D-AP5 was concentration dependent, with an EC50 of 10 microM. Up-regulation of NMDA receptors was observed after 2-7 days but not after 1 day of exposure to 100 microM D-AP5. The density of NMDA receptors was also increased after exposure of cells to CGS 19755 and MK-801 but not after exposure to the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. The binding of [3H]AMPA was unaltered after exposure to D-AP5. These results demonstrate that the density of NMDA receptors on cultured neurons can be selectively up-regulated by exposure to NMDA receptor antagonists. Increases in the density of NMDA receptors occurring in vivo could complicate therapeutic approaches to the treatment of neurological disorders.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cells, Cultured; Cerebral Cortex; Dizocilpine Maleate; Neurons; Pipecolic Acids; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate; Up-Regulation

In monocular vision, frogs display a unidirectional optokinetic nystagmus (OKN), reacting only to temporal-nasal (T-N) stimulation. The OKN N-T component is almost absent. However, prolonged monocular visual deprivation by unilateral eyelid suture provoked the appearance of the N-T component. The analysis of search coil recordings showed that the slow phase velocity gain of both T-N and N-T components became similar. Chronic administration of N-methyl-D-aspartate (NMDA) antagonists for the duration of deprivation prevented the appearance of a symmetrical monocular OKN in frogs: following repeated intraperitoneal injections of either MK 801, CGS 19755 or intrapretectal microinjections of 2-amino-5-phosphonovalerate (APV), the N-T component did not appear, and OKN remained asymmetrical. Thus NMDA receptors appear to be involved in the control of the plasticity process which allows monocular OKN of adult lower vertebrates to become symmetrical.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dizocilpine Maleate; Injections, Intraperitoneal; Magnetics; Microinjections; N-Methylaspartate; Nystagmus, Physiologic; Pipecolic Acids; Rana esculenta; Receptors, N-Methyl-D-Aspartate; Vision, Monocular

ES-242-1 approximately 5 are novel microbial bioxanthracenes which do not contain nitrogen. The ES-242s inhibited the binding of [3H]TCP and [3H]CGS19755 to the N-methyl-D-aspartate (NMDA) receptor complex. They had no effect on the binding of the specific ligands for the non-NMDA receptor. The biochemical and pharmacological properties of ES-242-1 were fully examined since it is the most potent of the five compounds. ES-242-1 is highly specific for the NMDA receptor; it has no effect on other receptors. Kinetic analyses indicated that ES-242-1 inhibited the binding of [3H]TCP and [3H]CGS19755 in a competitive manner, respectively, suggesting that ES-242-1 interacts with both the transmitter recognition site and the channel domain. ES-242-1 selectively inhibited NMDA-induced Ca2+ influx in primary cultures of mouse hippocampal neurons. ES-242-1 also specifically blocked the increase in cyclic GMP accumulation induced by NMDA or L-glutamate in rat cerebellar slices. In a concentration range of 0.1-1.0 microM, ES-242-1 was as potent as MK-801 in preventing glutamate-induced neurotoxicity in primary cultures of mouse hippocampal neurons. These results show that ES-242-1 is a potent and specific antagonist for the NMDA receptor. The antagonistic properties of the ES-242s appear to be due to a novel mechanism of action at the NMDA receptor.

Topics: Animals; Binding, Competitive; Biological Transport; Calcium; Cells, Cultured; Cyclic GMP; Dizocilpine Maleate; Hippocampus; Ion Channels; Kinetics; Mice; N-Methylaspartate; Neurons; Neurotransmitter Agents; Phencyclidine; Pipecolic Acids; Pyrans; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Synaptic Membranes

Topics: Animals; Discrimination, Psychological; Dizocilpine Maleate; Ethanol; Phencyclidine; Pipecolic Acids; Piperazines; Rats; Receptors, N-Methyl-D-Aspartate; Reinforcement, Psychology

A 5-min period of cerebral ischemia increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) assessed by the working memory procedure applied in a three-panel runway task. The selective and competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGS 19755 (3.2 and 10 mg/kg), administered i.p. immediately after blood flow reperfusion, significantly reduced the increase in errors expected to occur 24 h after 5 min of ischemia. CGS 19755 10 mg/kg had no effect on the increase in errors when injected 6 h after ischemia. The i.p. administration of the non-competitive NMDA antagonists dextrorphan 10 and 32 mg/kg and MK-801 1.0 mg/kg immediately after reperfusion decreased the increase of errors in the ischemic rats. The protective effects of NMDA antagonists suggest that the mechanism mediated by NMDA receptors during the early reperfusion phase plays a pivotal role in the postischemic impairment of working memory.

Topics: Animals; Dextrorphan; Dizocilpine Maleate; Ischemic Attack, Transient; Memory; N-Methylaspartate; Pipecolic Acids; Prosencephalon; Rats; Receptors, N-Methyl-D-Aspartate

The effects of the competitive NMDA (N-methyl-D-aspartate) receptor antagonist CGS 19755 and the non-competitive NMDA receptor antagonist dizocilpine (MK 801) on time discrimination and short-term memory were investigated in rats trained on a delayed time discrimination task. In a two-lever operant chamber, pressing one lever was correct and reinforced with a food pellet after presentation of a stimulus light for 2 s (SD(short)); pressing the opposite lever was correct after presentation of a stimulus light for 8 s (SD(long)). CGS 19755 (3.0 mg/kg) attenuated performance, decreased nose-pokes (an activity necessary to trigger the presentation of the discriminative stimulus and the presentation of the response levers), and increased response latencies (time from 'opportunity to leverpress' to 'actual leverpress'). The highest dose of dizocilpine (0.2 mg/kg) tested also attenuated performance. Further, the number of nose-pokes and response latencies were not altered by any dose of dizocilpine. With increasing delays, saline-injected animals developed a bias towards reporting an occurrence of an SD(long), independent of the actual stimulus presented. This bias was attenuated or even reversed by CGS 19755 (3.0 mg/kg) and (0.2 mg/kg). Our results suggest that NMDA receptors are directly or indirectly involved in time discrimination performance.

Topics: Animals; Conditioning, Operant; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Hippocampus; Male; Mental Recall; N-Methylaspartate; Pipecolic Acids; Rats; Rats, Wistar; Reaction Time; Receptors, N-Methyl-D-Aspartate; Reinforcement Schedule; Time Perception

Antagonists of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid (EAA) receptors blocked cocaine-induced stereotypy, locomotor stimulation and convulsions. These effects in general appear to involve selectively NMDA type of receptors. The results suggest that NMDA-activated systems are an integral component in the reaction sequences involved in the expression of several behavioral effects of cocaine.

Topics: Animals; Caffeine; Cocaine; Dextromethorphan; Dizocilpine Maleate; Haloperidol; Male; Mice; Mice, Inbred Strains; Motor Activity; N-Methylaspartate; Pipecolic Acids; Quinoxalines; Rats; Rats, Inbred Strains; Seizures; Stereoisomerism; Stereotyped Behavior

The administration of methamphetamine (METH) to experimental animals results in damage to nigrostriatal dopaminergic neurons. We have demonstrated previously that the excitatory amino acids may be involved in this neurotoxicity. For example, several compounds which bind to the phenyclidine site within the ion channel linked to the N-methyl-D-aspartate (NMDA) receptor protected mice from the METH-induced loss of neostriatal tyrosine hydroxylase activity and dopamine content. The present study was conducted to characterize further the role of the excitatory amino acids in mediating the neurotoxic effects of METH. The administration of three or four injections of METH (10 mg/kg) every 2 hr to mice produced large decrements in neostriatal dopamine content (80-84%) and in tyrosine hydroxylase activity (65-74%). A dose-dependent protection against these METH-induced decreases was seen with two noncompetitive NMDA antagonists, ifenprodil and SL 82.0715 (25-50 mg/kg/injection), both of which are thought to bind to a polyamine or sigma site associated with the NMDA receptor complex, and with two competitive NMDA antagonists, CGS 19755 (25-50 mg/kg/injection) and NPC 12626 (150-300 mg/kg/injection). Moreover, an intrastriatal infusion of NMDA (0.1 mumol) produced a slight but significant loss of neostriatal dopamine which was potentiated in mice that also received a systemic injection of METH. The results of these studies strengthen the hypothesis that the excitatory amino acids play a critical role in the nigrostriatal dopaminergic damage induced by METH.

Topics: Amino Acids; Animals; Corpus Striatum; Dizocilpine Maleate; Male; Methamphetamine; Mice; N-Methylaspartate; Pipecolic Acids; Piperidines; Receptors, Dopamine; Receptors, N-Methyl-D-Aspartate; Tyrosine 3-Monooxygenase

The non-competitive N-methyl-D-aspartate (NMDA) antagonists (channel blockers), MK 801, phencyclidine (PCP) and ketamine induced spontaneous tail-flicks in rats. Their order of relative potency (MK 801 greater than PCP greater than ketamine) corresponds to their relative affinities for the ion channel coupled to NMDA receptors. Drugs interacting with their other potential targets (sigma receptors as well as dopamine, serotonin and noradrenaline uptake sites) failed to induce spontaneous tail-flicks. In addition, the catecholamine stimulants, methylphenidate and cocaine were inactive. CPP and CGS 19755, antagonists at the NMDA recognition site, also dose dependently elicited spontaneous tail-flicks: their maximal effect was equal to that of the channel blockers. In contrast, HA-966 and ifenprodil, putative antagonists at the glycine and polyamine recognition sites, respectively, failed to elicit spontaneous tail-flicks. These data demonstrate that both antagonists of the NMDA recognition site and non-competitive blockers of the associated channel induce spontaneous tail-flicks in rats.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ion Channels; Ketamine; Male; N-Methylaspartate; Organophosphorus Compounds; Phencyclidine; Pipecolic Acids; Piperazines; Piperidines; Pyrrolidinones; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate

This study compared the ability of three N-methyl-D-aspartate (NMDA) receptor antagonists to prevent neuronal degeneration in an animal model of global cerebral ischemia. The model employed is characterized by damage to the striatum, hippocampus, and neocortex. Antagonists were administered to gerbils either before or after a 5-min bilateral carotid occlusion. The intraischemic rectal temperature was either maintained at 36-37 degrees C or allowed to fall passively to 28-32 degrees C. Antagonists and doses tested were 1 and 10 mg/kg of MK-801 (pre- or postischemia), 30 mg/kg of CGS 19755 preischemia, four 25 mg/kg doses of CGS 19755 administered between 0.5 and 6.5 h postischemia, and 40 mg/kg of MDL 27,266 (pre- or postischemia). All three NMDA receptor antagonists exhibited some degree of neuroprotective activity when the carotid occlusion was performed under normothermic conditions. Most of the treatments with antagonist markedly reduced striatal damage. CA1 hippocampal and neocortical pyramidal cells were spared by only three of the treatments, however, and the extent of neuroprotection varied widely from case to case. Toxic doses of antagonist were required to protect CA1 pyramidal cells from ischemic damage. Ischemic damage to hippocampal areas CA2-CA3a and CA4 appeared to be resistant to all of these treatments. Most CA1 pyramidal cells that were protected from degeneration by an NMDA receptor antagonist were histologically abnormal. The neuroprotective effects of MK-801 and intraischemic hypothermia appeared to be additive. MK-801 (10 mg/kg) consistently reduced the postischemic brain temperature, but only the magnitude of hypothermia produced soon after reperfusion correlated with its neuroprotective action. These results suggest that NMDA receptor antagonists are relatively poor neuroprotective agents against a moderately severe ischemic insult.

Topics: Animals; Body Temperature; Brain; Cerebral Cortex; Corpus Striatum; Dizocilpine Maleate; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Pipecolic Acids; Receptors, N-Methyl-D-Aspartate; Triazoles

The effects of non-competitive (MK-801, phencyclidine, and ketamine) and competitive (CGP 39551, CGS 19755, and NPC 12626) N-methyl-D-aspartate (NMDA) receptor antagonists on locomotor activity in inbred CBA and C57, and in outbred NMRI mice were examined. Administration of the non-competitive NMDA antagonists produced a dose-dependent increase in well-coordinated locomotor activity at lower doses, followed by a bizarre behavioral syndrome (head weaving, body rolling, rotations, ataxia) after higher doses. The pharmacological profile of the competitive antagonists CGP 39551, CGS 19755, and NPC 12626 was more complex. CGP 39551 dose-dependently inhibited locomotor activity, whereas CGS 19755 and NPC 12626 displayed a biphasic action, that is low doses inhibited locomotor activity, whereas higher doses produced mild behavioral stimulation. The behavioral effects of NMDA antagonists appear to be genetically determined, since CBA animals were most sensitive to both non-competitive and competitive antagonists, followed by NMRI and C57 animals. The differential effects of NMDA antagonists in various strains of mice suggest that the observed behavioral differences may be due to genetic differences in the NMDA/glutamate receptor channel complex.

Topics: Amino Acids; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Ketamine; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Motor Activity; Phencyclidine; Pipecolic Acids; Receptors, N-Methyl-D-Aspartate; Species Specificity

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.

Topics: Acoustic Stimulation; Amino Acids; Animals; Dizocilpine Maleate; Ligands; Male; N-Methylaspartate; Pipecolic Acids; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Reflex; Reflex, Startle

In the present study, comparative studies of the effects of competitive and noncompetitive antagonists of NMDA receptors (CPP, CGS19755 and MK-801) on two models of neuronal plasticity, kindling and long-term potentiation (LTP), were performed in rats. Systemic administration of CPP (5, 10 mg/kg), CGS19755 (5, 10 mg/kg) or MK-801 (1, 2 mg/kg) strongly retarded kindling development from the amygdala (AM), in which the early stage of kindled seizures and the growth of afterdischarges (ADs) recorded from the AM were significantly suppressed. After establishment of kindling, however, these compounds only reduced the previously AM-kindled seizure stage without shortening the AD duration. These NMDA receptor antagonists with the same dose sufficient for suppressing AM kindling almost completely blocked LTP of the synaptic component in the hippocampal dentate gyrus following high-frequency trains of the perforant path in urethane-anesthetized rats. These results further support the hypothesis that neuronal plasticity is induced by activation of the NMDA receptor complex and one of the basic neuronal mechanisms underlying kindling may be a long-lasting increase in synaptic transmission.

Topics: Animals; Binding, Competitive; Dizocilpine Maleate; Electric Stimulation; Evoked Potentials; Kindling, Neurologic; Male; Neuronal Plasticity; Pipecolic Acids; Piperazines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate

1. We have investigated the modulation of N-methyl-D-aspartate (NMDA) receptor activation by the sulphydryl redox reagents dithiothreitol (DTT) and 5,5-dithio-bis-2-nitrobenzoic acid (DTNB). 2. Increases in [3H]-MK-801 binding produced by glutamate, glycine and spermidine were enhanced by DTT (2mM) and diminished by DTNB (0.5 mM). 3. The inhibition of [3H]-MK-801 binding by CGS 19755 and 7-chlorokynurenate was not altered by 2 mM DTT. However, the potency of the competitive polyamine antagonist, arcaine, was decreased by DTT. 4. NMDA-induced Ca2+ fluxes into primary cultures of rat forebrain neurones were enhanced by DTT in a DTNB-reversible fashion. In addition to augmenting the magnitude of NMDA-induced increase in intracellular free Ca2+, 10 mM DTT also prolonged the duration of the Ca2+ signal. However, DTT had no effect on the increase in Ca2+ produced by depolarizing neurones with 50 mM KCl. 5. These studies show that the reduction of disulphide bonds on the NMDA receptor complex by DTT increases activation. The precise site of these groups remains unclear but they are unlikely to form an integral part of the glutamate, glycine or polyamine binding domains. The enhancement of the activation of the NMDA receptor by DTT is associated with increased Ca2+ fluxes. The possible pathophysiological consequences of receptor reduction are discussed.

Topics: Animals; Calcium; Dithionitrobenzoic Acid; Dithiothreitol; Dizocilpine Maleate; Fluorescence; Fura-2; Glutamates; Glycine; In Vitro Techniques; Kynurenic Acid; N-Methylaspartate; Pipecolic Acids; Rats; Receptors, N-Methyl-D-Aspartate; Spermidine

Topics: Animals; Anticonvulsants; Body Temperature; Brain; Brain Diseases; Carotid Arteries; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Gerbillinae; Hippocampus; Hypothermia; Ischemic Attack, Transient; Male; Pipecolic Acids; Pyramidal Tracts; Receptors, N-Methyl-D-Aspartate; Triazoles

The role of N-methyl-D-aspartate (NMDA) receptors in memory processes was examined using a Y-shaped maze and a step-through passive avoidance task in mice. In the Y-maze, the total number of arm entries, which represents locomotor activity and alternation behaviour, thought to reflect working memory, were measured. Competitive NMDA antagonists, CGS 19755 (cis-4-phosphonomethyl-2-piperidine-carboxylate) and CPP (3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphate), impaired spontaneous alternation at doses which reduced locomotion of mice. N-Methyl-D-aspartate prevented the impairment of alternation and decrease of locomotor activity produced by CGS 19755 and CPP. These results suggest that NMDA-dependent processes are involved in the mechanisms of working memory. In contrast, the non-competitive NMDA antagonist, MK 801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate) dramatically enhanced the total number of arm entries, while reducing alternation behaviour, N-Methyl-D-aspartate had no effect on MK 801-induced enhancement of locomotor activity and impairment of alternation. In the passive avoidance task, mice were trained to avoid entry into the dark compartment. At doses which impaired working memory in the alternation task, CPP, CGS 19755 and MK-801 reduced acquisition, when administered before training. N-Methyl-D-aspartate antagonized the effect of CPP, CGS 19755 and MK-801. Neither CPP nor MK-801 affected retention, when administered immediately after training or before testing retention. N-Methyl-D-aspartate had no effect on retention with high-intensity shock, but facilitated retention with low-intensity shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Avoidance Learning; Dizocilpine Maleate; Male; Memory; Mice; Motor Activity; N-Methylaspartate; Pipecolic Acids; Piperazines; Receptors, N-Methyl-D-Aspartate; Reference Values

Several lines of evidence suggest a tight functional coupling between N-methyl-D-aspartate (NMDA) and phencyclidine (PCP) receptors. The effects of PCP receptor agonists (PCP, dexoxadrol, ketamine and MK-801) and NMDA receptor antagonists, cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS-19755) and 3-(2-carboxypiperizin-4-yl)-propyl-1-phosphonic acid (CPP), have been examined on the metabolism of dopamine in the mesocortex, with a view of studying the coupling between these two receptor systems. Phencyclidine receptor agonists selectively increased the metabolism of dopamine in the mesocortex without affecting the metabolism of dopamine in the striatum. N-Methyl-D-aspartate and the competitive antagonists of NMDA receptors did not effect the metabolism of dopamine, neither did the sigma receptor ligands, 1,3-di-(2-tolyl)guanidine (DTG) and rimcazole. Rimcazole also did not affect the increases in the metabolism of dopamine in the mesocortex, seen after MK-801. These data indicate that dopaminergic neurons in the mesocortex are positively modulated by PCP receptors but tentatively suggest that those recognition sites for PCP are not coupled to NMDA receptors.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Brain Chemistry; Carbazoles; Cerebral Cortex; Dibenzocycloheptenes; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Guanidines; Ligands; Male; Neural Pathways; Pipecolic Acids; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Phencyclidine; Stereoisomerism

We have administered antagonists acting competitively or noncompetitively at the N-methyl-D-aspartate receptor after a short period of incomplete ischaemia and evaluated selective neuronal loss in the CA1 region of the rat hippocampus. The competitive antagonists D-(-)-2-amino-7-phosphonoheptanoate (2APH); 100 or 330 mg/kg; 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP); 3.3 or 10 mg/kg; and CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylate) 3.3 or 10 mg/kg; and the noncompetitive antagonists MK801 [+)5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), 0.3, 1, or 3 mg/kg, and dextrorphan, 2, 6, 18, or 54 mg/kg, were administered intraperitoneally 15 min and 5 h after a 10-min incomplete ischaemia period; additionally MK801 (1 or 3 mg/kg) and CGS 19755 (10 or 30 mg/kg) were administered 5 and 10 h postischaemia. Seven days after ischaemia, the brains were fixed by perfusion. CA1 pyramidal cell counts were performed on Nissl-stained sections using an ocular grid piece. Ventilated (no ischaemia) control animals had a mean of 406 +/- 13 CA1 neurones/3 grid lengths. Ischaemia reduced this mean to 157 +/- 23. A significant protective effect against this cell loss was seen after two injections (at 15 min and 5 h postischaemia) of 2APH, CPP (10 mg/kg), CGS 19755 (10 mg/kg), MK801 (1 mg/kg), and dextrophan (54 mg/kg). Delayed injection (5 and 10 h postischaemia) of CGS 19755 (10 and 30 mg/kg) and MK801 (1 and 3 mg/kg) did not provide any protection against pyramidal cell loss.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Anticonvulsants; Aspartic Acid; Brain; Brain Ischemia; Dibenzocycloheptenes; Dizocilpine Maleate; Male; N-Methylaspartate; Neurons; Pipecolic Acids; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

The effects of excitatory amino acid antagonists on convulsions induced by intracerebroventricular (i.c.v.) or systemic (s.c.) administration of the gamma-aminobutyric acidA (GABAA) antagonist bicuculline (BIC) were tested in mice. 3-[+/-)-2-Carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP), 2-amino-7-phosphonoheptanoate (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cycloheptan-5,10-imine maleate (MK-801) were used as representatives of N-methyl-D-aspartate (NMDA) antagonists. gamma-D-Glutamylaminomethylsulphonate (gamma-D-GAMS) typified a preferential kainate (KA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) represented a preferential quisqualate (QA) antagonist, and kynurenic acid (KYNA) was used as a mixed NMDA/KA antagonist. Bicuculline methiodide (BMI) induced clonic convulsions following i.c.v. administration with a CD50 of 0.183 nmol (range 0.164-0.204). The excitatory amino acid antagonists blocked clonic seizures induced by BMI in the dose of 0.224 nmol (approximately CD97) when coinjected into the lateral ventricle. CPP (ED50 0.0075 nmol) was the most potent anticonvulsant and was followed by AP7 (0.182 nmol), MK-801 (0.22 nmol), gamma-D-GAMS (0.4 nmol), KYNA (1.7 nmol) and CNQX (5.17 nmol). Muscimol (MSC), the GABAA agonist, blocked BMI-induced seizures with an ED50 of 0.25 nmol. Systemic (s.c.) administration of BIC induced in mice generalized seizures with a CD50 of 2.2 mg/kg (range 1.9-2.5) for clonus and CD50 of 2.4 mg/kg (range 2.2-2.7) for tonus.2+ the pathogenesis of seizures triggered by bicuculline in mice.

Topics: Animals; Bicuculline; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Mice; Muscimol; Pipecolic Acids; Piperazines; Piperidines; Receptors, Amino Acid; Receptors, Cell Surface; Seizures

The in vivo efficacies and potencies of various excitatory amino acid agonists in inducing cholinergic neuronal degeneration were compared following unilateral injections into the rat striatum. Kainic acid (KA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), ibotenic acid (IBO), and N-methyl-D-aspartic acid (NMDA) all produced dose-related decreases in choline acetyltransferase (ChAT) activity. The relative order of potency was KA greater than AMPA greater than IBO greater than NMDA. Quisqualic acid (QUIS) was about as potent as NMDA, but the maximal decrease in ChAT activity was less (36%). N-acetylaspartyl-L-glutamate (NAAG) did not significantly decrease ChAT activity when up to 1,000 nmoles was injected. Approximate equitoxic doses of agonists were then used to examine the ability of i.p. administered CGS-19755 and MK-801 to prevent in vivo excitatory amino acid-induced cholinergic and GABAergic neuronal degeneration. NMDA-induced decreases in ChAT and glutamic acid decarboxylase (GAD) activities were prevented by CGS-19755 (10-40 mg/kg) and MK-801 (1-10 mg/kg). CGS-19755 (40 mg/kg) and MK-801 (10 mg/kg) did not prevent loss of ChAT or GAD induced by KA or AMPA, but did prevent the degenerative effects of IBO. This study shows that CGS-19755 and MK-801, two NMDA receptor antagonists that act by different mechanisms, are completely selective following systemic administration. Moreover, the in vivo excitotoxic effects of IBO are mediated at NMDA receptor sites that are blocked by these compounds.

Topics: Animals; Aspartic Acid; Choline O-Acetyltransferase; Cholinergic Fibers; Corpus Striatum; Dibenzocycloheptenes; Dizocilpine Maleate; gamma-Aminobutyric Acid; Ibotenic Acid; Male; N-Methylaspartate; Nerve Degeneration; Oxazoles; Pipecolic Acids; Piperidines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

The purported competitive excitatory amino acid antagonist CGS 19755 was compared to the non-competitive antagonists ketamine and MK-801 in three rhesus monkeys discriminating between 1.78 mg/kg of ketamine and saline while responding under a fixed-ratio 100 schedule of food presentation. MK-801 substituted completely for the ketamine discriminative stimulus and was 32 times more potent than ketamine as a discriminative stimulus. CGS 19755 was studied using single and cumulative dosing procedures up to a dose of 10.0 mg/kg; for all conditions, CGS 19755 produced responding exclusively on the saline lever and had only modest rate-decreasing effects. N-Methyl-D-aspartate administered alone also did not produce ketamine-appropriate responding but did decrease response rates in a dose-related manner. N-Methyl-D-aspartate eliminated responding in all monkeys at doses of 5.6-10.0 mg/kg. MK-801 and ketamine antagonized the rate-decreasing effects of N-methyl-D-aspartate, however, ketamine was most effective as an antagonist at doses that decreased response rates when administered alone. CGS 19755 also attenuated the rate-decreasing effects of N-methyl-D-aspartate and shifted the N-methyl-D-aspartate dose-effect curve more than 5-fold to the right. The magnitude of antagonism of N-methyl-D-aspartate appeared to be somewhat greater with CGS 19755 than with MK-801 or ketamine. Thus, a competitive (CGS 19755) and some non-competitive (MK-801 and ketamine) excitatory amino acid antagonists can attenuate the rate-decreasing effects of N-methyl-D-aspartate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticonvulsants; Aspartic Acid; Dibenzocycloheptenes; Discrimination, Psychological; Dizocilpine Maleate; Ketamine; Macaca mulatta; Male; N-Methylaspartate; Pipecolic Acids; Piperidines