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Considerable reduction of the N-methyl-D-aspartate (NMDA) receptor channel current occurs when the mouse epsilon-1 subunit gene is subjected to targeted disruption. The targeted disruption also results in long-term potentiation at the hippocampal CA1 synapses. The NMDA receptor channel is involved in synaptic plasticity and helps maintain the process of memory, learning and development in mice and other higher-order animals. The targeted disruption causes a deficiency in spatial learning.

Deltamethrin is a type II pyrethroid insecticide which affects protein phosphorylation in rats. Total protein phosphorylation increased in rats that were subjected to deltamethrin as indicated by examinations of striatal slices of their brains. Deltamethrin also diminished the effects of forskolin stimulation on protein phosphorylation. Without forskolin, NMDA and deltamethrin acted as stimulants.

Excitatory amino acid (EAA) receptors are an important component of neocortical circuitry as a result of their role as the principal mediators of excitatory synaptic activity, as well as their involvement in use-dependent modifications of synaptic efficacy, excito-toxicity and cell death. The diversity in the effects generated by EAA-receptor activation can be attributed to multiple receptor subtypes, each of which is composed of multimeric assemblies of functionally distinct receptor subunits. The use of subunit-specific antibodies and molecular probes now makes it feasible to localize individual receptor subunits anatomically with a high level of cellular and synaptic resolution. Initial studies of the distribution of immunocytochemically localized EAA-receptor subunits suggest that particular subunit combinations exhibit a differential cellular, laminar and regional distribution in the neocortex. While such patterns might indicate that the functional heterogeneity of EAA-receptor-linked circuits, and the cell types in which they operate, are based partly on differential subunit parcellation, a definitive integration of these anatomical details into current schemes of cortical circuitry and organization awaits many further studies. Ideally, such studies should link a high level of molecular precision regarding subunit localization with synaptic details of identified connections and neuro-chemical features of neocortical cells.

Depolarization of crayfish axon terminals to different concentrations of glutamate and N-methyl-D-aspartate (NMDA) neuroreceptors reveals the presynaptic effects of both the receptors on the discharge of neurotransmitter in the terminals. Glutamate lowers the release at small depolarizing pulses, while the discharge is enhanced at large depolarizing pulses. Neurotransmitter release is lowered by NMDA at small depolarizing pulses, while it remains unaffected by NMDA at larger pulses.

Dynorphin A (dynA) and related opioid peptides produce moderate analgesic effects with restricted types of pain stimuli that are often accompanied by a large variety of naloxone-insensitive biochemical and behavioural effects. In binding assays in vitro, dynA possesses a high affinity for [Mu]-, [Delta]- and [Kappa]- opioid receptors with some selectivity for [Kappa] sites, but it also binds to specific non-opioid sites. The involvement of the NMDA receptor has been suggested to explain some of the non-opioid effects of dynA and related peptides. In this article, Vijay Shukla and Simon Lemaire review the experimental evidence that suggests a role for the NMDA receptor in some of the pharmacological effects of dynA and related peptides.

Adenosine is present in the mammalian brain in large amounts and has potent effects on neuronal activity, but its role in neural signaling is poorly understood. The glutamate receptor agonist N-methyl-D-aspartate (NMDA) caused a presynaptic depression of excitatory synaptic transmission in the CA1 region of guinea pig hippocampal slices. This depression was blocked by an adenosine A1 receptor antagonist, which suggests that activation of the NMDA subtype of glutamate receptor raises the concentration of extracellular adenosine, which acts on presynaptic inhibitory A1 receptors. Strong tetanic stimulation caused a heterosynaptic inhibition that was blocked by both NMDA and A1 receptor antagonists. Enkephalin, which selectively inhibits interneurons, antagonized the heterosynaptic inhibition. These findings suggest that synaptically released glutamate agtivates NMDA receptors, which in turn releases adenosine, at least in part from interneurons, that acts at a distance to inhibit pre-synaptically the release of glutamate from excitatory synapses. Thus, interneurons may mediate a widespread purinergic presynaptic inhibition., Adenosine is a purine that is present in large amounts in the mammalian brain (1). When applied to brain slices, adenosine exerts a powerful presynaptic inhibition of excitatory synaptic transmission, [...]

D(1) dopamine (DA) and N-methyl-D-aspartate (NMDA) receptor activation mediates morphine stimulation of the c-fos and junB immediate early gene (IEG) in striatum and nucleus accumbens (NA). This stimulation is similar to those for cocaine and amphetamine. In situ hybridization studies show that morphine induction occurs only in medial and ventral striatum. D1 and NMDA receptor antagonists inhibit morphine induction of IEG in striatum and NA and do not prevent the induction in septum, revealing different brain region mediation for different opiate behaviors.

Analysis of the drugs L-AP4 and the mGluR agonist 1S,3R-ACPD, obtained from mudpuppy ON bipolar cells, reveals that the two drugs close the same ion channel, produce similar currents and act through the same intracellular pathway. cGMP-PDE inhibitors suppress responses to both drugs. The results indicate that 15, 3R-ACPD is an agonist at L-AP4 receptors. The similar rank-order potencies of ACPD enantiomers at retinal L-AP4 receptors and non- AP4 mGluRs in the brain reveal that the binding sites of retinal L-AP4 receptors and brain non-AP4-mGluRs are identical.

Inhibitors of an endogenous serine/threonine phosphatase increase the period of single NMDA channel openings. Inhibitors such as okadaic acid and calcineurin, involved by calcium entry through NMDA channels, reduce the period of channel openings. The consistency of phosphorylation of NMDA complex and phosphatase inhibition, which improves simulated synaptic currents, influence short and long term control of neuronal excitability.

L-Glutamate and norepinephrine are examples of a major excitatory neurotransmitter and a neuromodulator in the cerebral cortex, respectively. Little is known of how chemical signaling between the anatomically distinct chemical pathways occurs. Specific activation of the N-methyl-D-aspartate (NMDA) class of glutamate receptor in synaptosomal preparations from guinea pig cerebral cortex caused release of both of these chemicals, and this release was blocked by agents that inhibit nitric oxide (NO) production or remove NO from the extracellular space. Furthermore, neurotransmitter release correlated with cortical NO production after NMDA receptor stimulation. These results suggest that NO production and its extracellular movement may be links in the pathway from NMDA receptor activation to changes in chemical signaling in surrounding synaptic terminals in the cerebral cortex., Activation of the NMDA glutamate receptor on neurons in the vertebrate central nervous system is important for excitatory synaptic transmission (1, 2), developmental and synaptic plasticity (2, 3), and neurotoxicity [...]

The mechanism of an excitatory neurotransmitter in the brain, cholecystokinin (CKK), includes the action of CCK-8S, the sulfated octapeptide, in eliminating cAMP-dependent phosphorylation of a dopamine- and cAMP-regulated 32-kDa phosphoprotein (DARPP-32) in striatal neurons. Antagonists of CCKB and N-methyl-D-asparate receptors inhibit the action of CCK-8S. CCK-8S, obtained from CCK or CCK/glutamate cortico-striatal neurons, enhances the secretion of an excitatory neurotransmitter which induces dephospohrylation and activation of DARPP-32, and so regulates the excitability of neurons.

Several acute and chronic neurological diseases might be mediated, at least in part, via stimulation of excitatory amino acid receptors, such as the N-methyl-D-aspartate (NMDA) receptor. Antagonists of excitatory amino acid receptors ameliorate neurotoxic damage in several animal models of these disorders. This review focuses on the potential for clinically tolerated NMDA receptor antagonists, with emphasis on agents that have been in clinical use for other conditions and that recently have been shown to inhibit NMDA receptor activity by a mechanism of open-channel block or redox modification.

Long-term potentiation in the CA1 region of the hippocampus is the most extensively studied model of activity-dependent synaptic plasticity in the mammalian brain. Its induction normally involves activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors, which are thought to control the occurrence of long-term potentiation at individual synapses. Recent work in the hippocampus indicates that NMDA receptor activation does not necessarily lead to induction of long-term potentiation but instead may elicit a repertoire of distinct forms of synaptic plasticity including short-term potentiation or long-term depression. Furthermore, mechanisms exist such that the induction of long-term potentiation can be inhibited by modest activation of NMDA receptors. Experimental results are beginning to clarify the mechanistic relationships between these different phenomena, although much remains unknown. Whatever their underlying mechanisms, these additional forms of NMDA-receptor-dependent synaptic plasticity confer increased flexibility to neural circuits involved in information processing and storage.

The glycine site on the NMDA receptor complex has generated an enormous amount of interest since it was first described five years ago. In this review by John Kemp and Paul Leeson the structure-activity relationships of agonists, partial agonists and antagonists acting at the glycine site are reviewed, along with what has been learned from studies with these compounds about the role of this site in physiological and pathological processes. Studies with prototype antagonists, and low-efficacy partial agonists that penetrate the brain, show that these compounds possess anticonvulsant and neuroprotective properties but lack some of the side-effects of other types of NMDA antagonists.

The extinction of conditioned fear memories requires plasticity in the infralimbic medial prefrontal cortex (IL mPFC), but little is known about the molecular mechanisms involved. Brain-derived neurotrophic factor (BDNF) is a key mediator of synaptic plasticity in multiple brain areas. In rats subjected to auditory fear conditioning, BDNF infused into the IL mPFC reduced conditioned fear for up to 48 hours, even in the absence of extinction training, which suggests that BDNF substituted for extinction. Similar to extinction, BDNF-induced reduction in fear required N-methyl-D-aspartate receptors and did not erase the original fear memory. Rats failing to learn extinction showed reduced BDNF in hippocampal inputs to the IL mPFC, and augmenting BDNF in this pathway prevented extinction failure. Hence, boosting BDNF activity in hippocampal-infralimbic circuits may ameliorate disorders of learned fear. 10.1126/science.1186909

The distribution of N-methyl-D-aspartate receptors in the develoing rat spinal cord was mapped using quantitative receptor autoradiography. It was shown that N-methyl-D-aspartate receptors are expressed in the ventral horn of young animals and that the distribution changes dramatically over the first two weeks of life. These results reflect the role of N-methyl-D-aspartate receptors in motor neuron development during the early weeks of fetal life.

The effects ofMK-801 on the expression of c-fos protein was analyzed in the context of its relationship to N-methyl-D-aspartate receptor-mediated neurodegeneration under pathological conditions. It was shown that transneuronal alterations are reduced by systemic injections of MK-801. MK-801 also blocks c-fos protein-likeimmunoreactivity which suggests that the NMDA receptor-mediated neurotoxicity due to postlesional glutamate elevation results in early gene expression and intransneuronal dendritic changes.

The purification of vertebrate excitatory amino acid ionotropic receptors from Xenopus central nervous system showed the presence of a unitary non-N- methyl-D-aspartate (NMDA) receptor and a unitary L-kainic acid (KA)/alpha-amino3-hydroxy-5-methylisooxazole-proprionate/NMDA receptor. The isolated protein was reconstituted and the specific agonist-activated channel activity and pharmacology of each receptor type were identified using patch-clamping lipid bilayers.

Restoration of the Plasticity of Binocular Maps by NMDA After the Critical Period in Xenopus VISUAL EXPERIENCE CAN HAVE A major impact on the developing axonal connections of the visual [...]