dizocilpine-maleate and 5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1-4-dihydroquinoxaline-2-3-dione

Cannabis affects cognitive performance through the activation of the endocannabinoid system, and the molecular mechanisms involved in this process are poorly understood. Using the novel object-recognition memory test in mice, we found that the main psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), alters short-term object-recognition memory specifically involving protein kinase C (PKC)-dependent signaling. Indeed, the systemic or intra-hippocampal pre-treatment with the PKC inhibitors prevented the short-term, but not the long-term, memory impairment induced by THC. In contrast, systemic pre-treatment with mammalian target of rapamycin complex 1 inhibitors, known to block the amnesic-like effects of THC on long-term memory, did not modify such a short-term cognitive deficit. Immunoblot analysis revealed a transient increase in PKC signaling activity in the hippocampus after THC treatment. Thus, THC administration induced the phosphorylation of a specific Ser residue in the hydrophobic-motif at the C-terminal tail of several PKC isoforms. This significant immunoreactive band that paralleled cognitive performance did not match in size with the major PKC isoforms expressed in the hippocampus except for PKCθ. Moreover, THC transiently enhanced the phosphorylation of the postsynaptic calmodulin-binding protein neurogranin in a PKC dependent manner. These data demonstrate that THC alters short-term object-recognition memory through hippocampal PKC/neurogranin signaling.

Topics: Animals; Anisomycin; Dizocilpine Maleate; Dose-Response Relationship, Drug; Dronabinol; Drug Interactions; Hippocampus; Isoenzymes; Male; Memory, Short-Term; Mice; Microinjections; Neurogranin; Phenols; Phosphorylation; Piperidines; Protein Kinase C; Quinoxalines; Rimonabant; Signal Transduction; Sirolimus

Destabilization refers to a memory that becomes unstable when reactivated and is susceptible to disruption by amnestic agents. Here we delineated the cellular mechanism underlying the destabilization of drug memory. Mice were conditioned with methamphetamine (MeAM) for 3 d, and drug memory was assessed with a conditioned place preference (CPP) protocol. Anisomycin (ANI) was administered 60 min after the CPP retrieval to disrupt reconsolidation. We found that destabilization of MeAM CPP after the application of ANI was blocked by the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801 and the NR2B antagonist ifenprodil (IFN) but not by the NR2A antagonist NVP-AAM077 (NVP). In addition, decrease in the phosphorylation of GluR1 at Serine845 (p-GluR1-Ser845), decrease in spine density, and a reduction in the AMPAR/NMDAR ratio in the basolateral amygdala (BLA) were reversed after the MK-801 treatment. The effect of ANI on destabilization was prevented by the protein phosphatase 2B (calcineurin, CaN) inhibitors cyclosporine A (CsA) and FK-506 and the protein phosphatase 1 (PP1) inhibitors calyculin A (CA) and okadaic acid (OA). These results suggest that memory destabilization involves the activation of NR2B-containing NMDARs, which in turn allows the influx of Ca(2+) Increased intracellular Ca(2+) stimulates CaN, leading to the dephosphorylation and inactivation of inhibitor 1 and the activation of PP1. PP1 then dephosphorylates p-GluR1-Ser845 to elicit AMPA receptor (AMPAR) endocytosis and destabilization of the drug memory.

Topics: Amygdala; Animals; Anisomycin; Calcium Signaling; Conditioning, Classical; Dendritic Spines; Dizocilpine Maleate; Male; Memory Consolidation; Mental Recall; Methamphetamine; Mice, Inbred C57BL; Phosphoprotein Phosphatases; Protein Synthesis Inhibitors; Quinoxalines; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate

Ischemic postconditioning (Post C), which involves administration of a brief ischemia after the initial ischemic event, has been demonstrated to be strongly neuroprotective against global cerebral ischemia (GCI) and to improve cognitive outcome. To enhance understanding of the underlying mechanisms, the current study examined the role of NMDA receptors in mediating the beneficial effects of Post C (3 min ischemia) administered 2 days after GCI in adult male rats. The results revealed that Post C was strongly neuroprotective against GCI, and that this effect was blocked by administration of the NMDA receptor antagonist MK-801. Further work revealed that the NR2A-type NMDA receptors mediate the Post C beneficial effects as administration of a NR2A-preferring antagonist (NVP-A) blocked Post C neuroprotection and cognitive enhancement, while administration of a NR2B-preferring antagonist (Ro25) was without effect. Post C significantly up-regulated NR2A levels and phosphorylation of NR2A in the hippocampal CA1 region after Post C. Post C also increased Ca(2+) influx and activation/phosphorylation of CamKIIα at Thr(286), effects that were NR2A mediated as they were blocked by NVP-A. Phosphorylation of ERK and CREB was also increased by Post C, as were two downstream CREB-dependent prosurvival factors, brain derived neurotropic factor (BDNF) and Bcl2, effects that were blocked by the NR2A antagonist, NVP-A. Taken as a whole, the current study provides evidence that NR2A-activation and downstream prosurvival signaling is a critical mediator of Post C-induced neuroprotection and cognitive enhancement following GCI.

Topics: Analysis of Variance; Animals; Brain Ischemia; Calcium; CREB-Binding Protein; Dizocilpine Maleate; Hippocampus; Immunoprecipitation; Male; Maze Learning; Neuroprotective Agents; Phenols; Piperidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Time Factors

N-methyl-D-aspartate (NMDA) receptors play crucial roles in learning and memory, but the role of each NMDA receptor subtype in a specific cognitive process is unclear. Non-selective blockers of NMDA receptor are used to model the cognitive impairment in schizophrenia and Alzheimer's disease. Counter-intuitively selective NR2A and 2B NMDA receptor antagonists are thought to have pro-cognitive properties. These seemingly contrasting findings might in part be the result of different compounds and behavioral measures used across studies.. We compared the effect of NVP-AAM077 (NR2A antagonist), CP 101-606 (NR2B antagonist), and MK-801 (non-selective antagonist) in a series of touch screen tasks that can be used to measure spatial cognition and cognitive flexibility.. NVP-AAM077, CP 101-606, and MK-801 were administered prior to testing, in adult male Lister-hooded rats trained in tasks of location discrimination, paired associate learning (PAL), and trial unique non-match to location (TUNL).. Results showed that MK-801 impaired performance on all the tasks. In contrast, CP 101-606 only impaired reversal learning in location discrimination and had minimal effect on working memory in TUNL and caused a modest improvement in accuracy in PAL and acquisition of a spatial discrimination. NVP-AAM077 had little effect on performance across tasks, although these data allude to a potential enhancement of acquisition of a spatial location and impairments in spatial reversal learning in a separation-dependent manner.. These data demonstrated that non-selective NMDA antagonism will disrupt numerous aspects of cognitive function. However, selective antagonism is capable of impairing or enhancing cognitive function in a task-dependent fashion.

Topics: Animals; Association Learning; Cognition; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Piperidines; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate; Spatial Memory

The emotion of despair that occurs with uncontrollable stressful event is probably retained by memory, termed despair-associated memory, although little is known about the underlying mechanisms. Here, we report that forced swimming (FS) with no hope to escape, but not hopefully escapable swimming (ES), enhances hippocampal α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-dependent GluA1 Ser831 phosphorylation (S831-P), induces a slow-onset CA1 long-term potentiation (LTP) in freely moving rats and leads to increased test immobility 24-h later. Before FS application of the antagonists to block S831-P or N-methyl-D-aspartic acid receptor (NMDAR) or glucocorticoid receptor (GR) disrupts LTP and reduces test immobility, to levels similar to those of the ES group. Because these mechanisms are specifically linked with the hopeless of escape from FS, we suggest that despair-associated memory occurs with an endogenous CA1 LTP that is intriguingly mediated by a unique combination of rapid S831-P with NMDAR and GR activation to shape subsequent behavioral despair.

Topics: Animals; CA1 Region, Hippocampal; Corticosterone; Depression; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Immunoblotting; Ketamine; Long-Term Potentiation; Male; Memory; Mineralocorticoid Receptor Antagonists; Phosphorylation; Quinoxalines; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glucocorticoid; Receptors, N-Methyl-D-Aspartate; Spironolactone; Stress, Psychological; Swimming

Neonatal hypoxia-ischemia brain damage is an important cause of death by affecting prognosis of neural diseases. It is difficult to find effective methods of prevention and treatment due to the complexity of its pathogenesis. N-methyl-D-aspartate (NMDA), as an excitotoxicity amino acids, has proven to play an important role in hypoxic-ischemic. However, the exact effects of the NMDA subunits, NR2A and NR2B, during hypoxic-ischemic have not been investigated in detail. Therefore, we sought to study whether the NMDA receptor antagonist could confer neuroprotective effects in a neonatal rat hypoxia-ischemia model. The effects of intraperitoneal injections of different drugs, namely MK-801 (0.5 mg/kg), NVP-AAM077 (5 mg/kg), and Ro25-6981 (5 mg/kg), on the expressions of anti-apoptotic protein Bcl-2 and apoptosis protein Bax in the subventricular zone were analyzed by immunohistochemical staining to explore the roles of NMDA subunits (NR2A and NR2B) in hypoxic-ischemic. We found that the NR2B antagonist (Ro25-6981) could inhibit hypoxic-ischemic with the increasing Bcl-2 expression. NR2A antagonists (NVP-AAM077) can increase cerebral hypoxia-ischemia in neonatal rats, promoting the expression of apoptotic protein Bax.

Topics: Animals; bcl-2-Associated X Protein; Disease Models, Animal; Dizocilpine Maleate; Hypoxia-Ischemia, Brain; Immunohistochemistry; Lateral Ventricles; Neuroprotective Agents; Phenols; Piperidines; Protein Subunits; Proto-Oncogene Proteins c-bcl-2; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

NMDA antagonists consistently produce social inhibition in adult animals, although effects of these manipulations on social behavior of adolescents are relatively unknown.. The aim of this study was to assess potential age differences in the socially inhibitory effects of the non-competitive NMDA antagonist, MK-801, as well as NR2 subunit selective effects, given the regional and developmental differences that exist for the NR2 subunit during ontogeny.. In separate experiments, adolescent and adult male Sprague-Dawley rats were treated acutely with MK-801 (0, 0.05, 0.1, 0.2 mg/kg, i.p.), the NR2A antagonist, PEAQX (2.5, 5, 10, 20 mg/kg, s.c.), or the NR2B antagonist, ifenprodil (1.5, 3, 6, 12 mg/kg, i.p.), 10 min prior to a social interaction test.. Adolescents required higher doses of MK-801 (0.1 and 0.2 mg/kg) to induce social suppression, whereas adults demonstrated reductions in social activity after all doses. Likewise, adolescents required higher doses of ifenprodil (6 and 12 mg/kg) to produce social inhibitory effects relative to adults (all doses). In contrast, adults were less sensitive to PEAQX than adolescents, with adults showing social inhibition after 20 mg/kg whereas adolescents showed this effect following 10 and 20 mg/kg. Although locomotor activity was generally reduced at both ages by all drugs tested, ANCOVAs using locomotor activity as a covariate revealed similar patterns of social inhibitory effects.. Adolescents are less sensitive than adults to the disruption of social behavior by NMDA and NR2B-selective receptor antagonism, but not by an NR2A antagonist-age differences that may be related to different subunit expression patterns during development.

Topics: Aging; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Inhibition, Psychological; Male; Motor Activity; Piperidines; Quinoxalines; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Social Behavior

Paradoxically, N-methyl-D-aspartate (NMDA) receptor antagonists are used to model certain aspects of schizophrenia as well as to treat refractory depression. However, the role of different subunits of the NMDA receptor in both conditions is poorly understood. Here we used biochemical and behavioral readouts to examine the in vivo prefrontal efflux of serotonin and glutamate as well as the stereotypical behavior and the antidepressant-like activity in the forced swim test elicited by antagonists selective for the GluN2A (NVP-AAM077) and GluN2B (Ro 25-6981) subunits. The effects of the non-subunit selective antagonist, MK-801; were also studied for comparison. The administration of MK-801 dose dependently increased the prefrontal efflux of serotonin and glutamate and markedly increased the stereotypy scores. NVP-AAM077 also increased the efflux of serotonin and glutamate, but without the induction of stereotypies. In contrast, Ro 25-6981 did not change any of the biochemical and behavioral parameters tested. Interestingly, the administration of NVP-AAM077 and Ro 25-6981 alone elicited antidepressant-like activity in the forced swim test, in contrast to the combination of both compounds that evoked marked stereotypies. Our interpretation of the results is that both GluN2A and GluN2B subunits are needed to induce stereotypies, which might be suggestive of potential psychotomimetic effects in humans, but the antagonism of only one of these subunits is sufficient to evoke an antidepressant response. We also propose that GluN2A receptor antagonists could have potential antidepressant activity in the absence of potential psychotomimetic effects.

Topics: Animals; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Phenols; Piperidines; Prefrontal Cortex; Quinoxalines; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Serotonin; Stereotyped Behavior

Adolescents display high levels of interactions with peers relative to other age groups, with these interactions further enhanced by ethanol under some circumstances. Understanding of the neural mechanisms underlying these high levels of social interactions is important given that alcohol use is initiated during adolescence and adolescents tend to report drinking for social reasons. Given that ethanol's effects are associated in part with functional antagonism of the NMDA receptor system, the current experiment explored the role of NMDA antagonists for facilitating adolescent social behavior. Adolescent male Sprague-Dawley rats were challenged acutely with either the non-competitive NMDA antagonist, MK-801 (0.01, 0.03mg/kg), the NR2A antagonist, PEAQX (1.25, 3.75mg/kg) or the NR2B antagonist, ifenprodil (0.75, 2.25mg/kg) 30min prior to a 10-min social interaction test. All compounds generally increased overall social activity (i.e., sum of social investigation, contact behavior, and play), with ifenprodil also significantly enhancing play and social contact behaviors. Although the frequencies of peer-directed social behaviors were typically greater following administration with these NMDA antagonists, social preference, indexed via the number of crossovers to the side with the partner relative to crossovers away, was significantly reduced in MK-801 and PEAQX-treated rats. None of these changes were associated with concomitant alterations in overall locomotor activity under these test circumstances. These data support the suggestion that the increases in social interactions observed in adolescents following acute ethanol may be driven in part by NMDA receptor antagonism - particularly of the NR2B subunit - given that ifenprodil stimulated social behavior in a manner similar to that produced by low doses of ethanol.

Topics: Animals; Behavior, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; N-Methylaspartate; Piperidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Social Facilitation

Converging evidence shows that monoamine oxidase A (MAO A), the key enzyme catalyzing serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) degradation, is a primary factor in the pathophysiology of antisocial and aggressive behavior. Accordingly, male MAO A-deficient humans and mice exhibit an extreme predisposition to aggressive outbursts in response to stress. As NMDARs regulate the emotional reactivity to social and environmental stimuli, we hypothesized their involvement in the modulation of aggression mediated by MAO A. In comparison with WT male mice, MAO A KO counterparts exhibited increases in 5-HT and NE levels across all brain regions, but no difference in glutamate concentrations and NMDAR binding. Notably, the prefrontal cortex (PFC) of MAO A KO mice exhibited higher expression of NR2A and NR2B, as well as lower levels of glycosylated NR1 subunits. In line with these changes, the current amplitude and decay time of NMDARs in PFC was significantly reduced. Furthermore, the currents of these receptors were hypersensitive to the action of the antagonists of the NMDAR complex (dizocilpine), as well as NR2A (PEAQX) and NR2B (Ro 25-6981) subunits. Notably, systemic administration of these agents selectively countered the enhanced aggression in MAO A KO mice, at doses that did not inherently affect motor activity. Our findings suggest that the role of MAO A in pathological aggression may be mediated by changes in NMDAR subunit composition in the PFC, and point to a critical function of this receptor in the molecular bases of antisocial personality.

Topics: Aggression; Animals; Antisocial Personality Disorder; Autoradiography; Binding Sites; Blotting, Western; Corpus Striatum; Dizocilpine Maleate; Electrophysiological Phenomena; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Male; Mice; Mice, Knockout; Monoamine Oxidase; Motor Activity; Norepinephrine; Patch-Clamp Techniques; Phenols; Piperidines; Prosencephalon; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Serotonin

Sub-anesthetic doses of NMDA receptor antagonists suppress sleep and elicit continuous high-power gamma oscillations lasting for hours. This effect is subunit-specific, as it was also seen after preferential blockade of the NR2A but not of the NR2B subunit-containing receptors. The objective of this study was to test whether NR2B receptor antagonists that do not induce lasting aberrant gamma elevation affect gamma activity during specific behaviors and states, including REM sleep, when gamma normally occurs.. Gamma oscillations in cortical EEG were assessed in different vigilance states in rats and were compared before and after injection of nonselective (ketamine, 10 mg/kg, and MK801, 0.2 mg/kg), as well as NR2A-preferring (NVP-AAM077, 20 mg/kg), and NR2B-selective NMDA receptor antagonists (Ro25-6985, 10 mg), and vehicle.. In contrast to nonselective and NR2A-preferring antagonists, Ro25-6985 did not disrupt sleep and had no effect on gamma activity during waking and slow wave sleep. It significantly increased, however, gamma power in the frontal (but not in occipital) cortex during REM sleep (by 37% ± 10%, average in the first 4 h). The effect had a short onset; enhanced gamma activity appeared as early as in the first REM sleep episode post-injection and lasted over 8 hours. Increased gamma power induced by MK-801 (46% ± 5%) and NVP-AAM077 (100% ± 8%) during REM sleep could also be detected several hours after injection when periodic alternation of sleep-wake states returned.. By acting on gamma oscillations in a state-dependent manner, NMDA receptors might have subunit-specific role in REM sleep-associated cognitive processes.

Topics: Animals; Arousal; Brain Waves; Dizocilpine Maleate; Electroencephalography; Ketamine; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate; Sleep, REM

The nucleoside adenosine (ADO) is a neuromodulator in brain. ADO and its metabolite inosine (INO) have been shown to increase cell viability in stroke models. During ischemia, extracellular levels of both ADO and INO are increased. In this study, we treated rat cortical neurons with N-methyl-D-aspartate (NMDA) to initiate excitotoxicity and then investigated the mechanisms of ADO and INO release. NMDA induced a significant increase in ADO and INO production. The effect of NMDA receptor antagonists on NMDA-evoked ADO and INO release was examined. MK-801 (1 micromol/L), a potent antagonist that lacks receptor subunit selectivity, completely blocked evoked release of both ADO and INO. Memantine (10 micromol/L), a lower affinity antagonist that also lacks subunit selectivity, blocked INO, but not ADO, release. Ifenprodil (10 micromol/L), an inhibitor selective for NMDA receptors containing the NR2B subunit, completely blocked evoked ADO and INO release. NVP-AAM077 (NVP, 0.4 micromol/L), an inhibitor selective for NMDA receptors containing the NR2A subunit, did not significantly block evoked release of either ADO or INO. Removal of extracellular Ca2+ abolished NMDA-evoked release of both ADO and INO. BAPTA (25 micromol/L), which chelates intracellular Ca2+, had no significant effect on either ADO or INO release unless extracellular Ca2+ was also removed. Inhibitors of Ca2+/calmodulin-dependent protein kinase II (CaMKII) prevented NMDA-evoked ADO and INO release and decreased nucleoside transporter function. These data indicate that NMDA-evoked ADO and INO release is dependent on subunit composition of NMDA receptors. As well, NMDA-evoked ADO and INO release requires nucleoside transporters and extracellular Ca2+ and is enhanced by activation of CaMKII.

Topics: Adenosine; Animals; Calcium; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cerebral Cortex; Chelating Agents; Dizocilpine Maleate; Egtazic Acid; Excitatory Amino Acid Antagonists; Inosine; N-Methylaspartate; Neurons; Piperidines; Purines; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate

NMDA receptors bidirectionally modulate extracellular signal-regulated kinase (ERK) through the coupling of synaptic NMDA receptors to an ERK activation pathway that is opposed by a dominant ERK shutoff pathway thought to be coupled to extrasynaptic NMDA receptors. In the present study, synaptic NMDA receptor activation of ERK in rat cortical cultures was partially inhibited by the highly selective NR2B antagonist Ro25-6981 (Ro) and the less selective NR2A antagonist NVP-AAM077 (NVP). When Ro and NVP were added together, inhibition appeared additive and equal to that observed with the NMDA open-channel blocker MK-801. Consistent with a selective coupling of extrasynaptic NMDA receptors to the dominant ERK shutoff pathway, pre-block of synaptic NMDA receptors with MK-801 did not alter the inhibitory effect of bath-applied NMDA on ERK activity. Lastly, in contrast to a complete block of synaptic NMDA receptor activation of ERK by extrasynaptic NMDA receptors, activation of extrasynaptic NMDA receptors had no effect upon ERK activation by brain-derived neurotrophic factor. These results suggest that the synaptic NMDA receptor ERK activation pathway is coupled to both NR2A and NR2B containing receptors, and that the extrasynaptic NMDA receptor ERK inhibitory pathway is not a non-selective global ERK shutoff.

Topics: Animals; Blotting, Western; Brain-Derived Neurotrophic Factor; Cells, Cultured; Cerebral Cortex; Cyclic AMP Response Element-Binding Protein; Dizocilpine Maleate; Enzyme Activation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Extracellular Signal-Regulated MAP Kinases; Extracellular Space; N-Methylaspartate; Neurons; Patch-Clamp Techniques; Phenols; Piperidines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction

Excitotoxicity is generally studied in dissociated neurons, cultured hippocampal slices, or intact animals. However, the requirements of dissociated neurons or cultured slices to use prenatal or juvenile rats seriously limit the advantages of these systems, whereas the complexity of intact animals prevents detailed molecular investigations. In the present experiments, we studied developmental changes in NMDA neurotoxicity in acute hippocampal slices with lactate dehydrogenase (LDH) release in medium, propidium iodide (PI) uptake, and Nissl staining as markers of cell damage. Calpain-mediated spectrin degradation was used to test calpain involvement in NMDA neurotoxicity. NMDA treatment produced increased LDH release, PI uptake, and spectrin degradation in slices from juvenile rats but not adult rats. NMDA-induced changes in slices from young rats were blocked completely by the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801) and by the antagonists of NR2B receptor ifenprodil and R-(R, S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol and were partly blocked by calpain inhibitor III but were not affected by the NR2A-specific antagonist [(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid. NMDA-induced changes in Nissl staining were also different in slices from young and adult rats and blocked by NR2B but not NR2A antagonists. In contrast to NMDA treatment, oxygen/glucose deprivation (OGD) induced neurotoxicity in slices from both young and adult rats, although OGD-induced toxicity was attenuated by MK-801 only in slices from young rats. Our results are consistent with the idea that NMDA-mediated toxicity is caused by activation of NR2B- but not NR2A-containing NMDA receptors leading to calpain activation and that developmental changes in NMDA toxicity reflect developmental changes in NMDA receptor subunit composition.

Topics: Age Factors; Animals; Biomarkers; Calpain; Dipeptides; Disks Large Homolog 4 Protein; Dizocilpine Maleate; Enzyme Activation; Excitatory Amino Acid Antagonists; Fluorescent Dyes; Gene Expression Regulation, Developmental; Glucose; Hippocampus; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; L-Lactate Dehydrogenase; Membrane Proteins; N-Methylaspartate; Neurons; Oxygen; Phenols; Piperidines; Propidium; Protein Subunits; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spectrin; Valine

It is widely believed that long-term depression (LTD) and its counterpart, long-term potentiation (LTP), involve mechanisms that are crucial for learning and memory. However, LTD is difficult to induce in adult cortex for reasons that are not known. Here we show that LTD can be readily induced in adult cortex by the activation of NMDA receptors (NMDARs), after inhibition of glutamate uptake. Interestingly there is no need to activate synaptic NMDARs to induce this LTD, suggesting that LTD is triggered primarily by extrasynaptic NMDA receptors. We also find that de novo LTD requires the activation of NR2B-containing NMDAR, whereas LTP requires activation of NR2A-containing NMDARs. Surprisingly another form of LTD, depotentiation, requires activation of NR2A-containing NMDARs. Therefore, NMDARs with different synaptic locations and subunit compositions are involved in various forms of synaptic plasticity in adult cortex.

Topics: 2-Amino-5-phosphonovalerate; Animals; Aspartic Acid; Cerebral Cortex; Dicarboxylic Acids; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Glutamic Acid; Long-Term Potentiation; Long-Term Synaptic Depression; N-Methylaspartate; Neurons; Neurotransmitter Uptake Inhibitors; Phenols; Picrotoxin; Piperidines; Protein Subunits; Pyrrolidines; Quinoxalines; Rats; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate