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D C Javitt

Publications and source records attributed to D C Javitt.

84 records · Page 5Linked to original sources
PubMed1990

The role of excitatory amino acids in neuropsychiatric illness.

Over the past several years, research has demonstrated that the excitatory amino acids serve as the major excitatory neurotransmitters in cerebral cortex and hippocampus. Neurons that contain excitatory amino acids play crucial roles in neuropsychological functioning, learning, and memory. In addition, these neurons exert descending control over subcortical structures that is behaviorally antagonistic to the effects mediated by the ascending dopaminergic system. Disturbances of excitatory amino acid systems may contribute to the pathogenesis of schizophrenia and to other neuropsychiatric syndromes associated with delirium or dementia.

Amino Acids↗
PubMed1990

Rat brain N-methyl-D-aspartate receptors require multiple molecules of agonist for activation.

N-Methyl-D-aspartate (NMDA) receptors mediate important physiological and pathological processes, including long term potentiation and neuronal excitotoxicity. Elucidation of mechanisms underlying NMDA receptor functioning will promote understanding of the molecular bases of NMDA receptor-mediated processes. The localization of the phencyclidine (PCP) receptor within the ionophore of the NMDA receptor-gated ion channel permits the binding of PCP receptor ligands to serve as a functional marker of channel activation. We have previously demonstrated that the highly selective PCP receptor ligand [3H]MK-801 displays multiexponential kinetics of association, indicating that the NMDA receptor functions according to a multistate model. Using the fast component of [3H]MK-801 binding to PCP receptors as a marker for activated NMDA channels, we demonstrate here a Hill coefficient of 2 for activation of NMDA channels by L-glutamate. A multistate model of NMDA receptor functioning analogous to the model known to account for the functioning of nicotinic cholinergic and gamma-aminobutyric acidA receptors fits well to our experimental data, supporting the concept that the NMDA receptor is properly classified in the Class 1 superfamily of ligand-gated channels.

Animals↗
PubMed1989

Glycine reverses 7-chlorokynurenic acid-induced inhibition of [3H]MK-801 binding.

7-Chlorokynurenic acid (7-Cl KYNA) has been reported to attenuate N-methyl-D-aspartate (NMDA) receptor functioning by a potent and selective inhibitory action mediated at the strychnine-insensitive glycine recognition site of the NMDA complex. Here we report that 7-Cl KYNA dose-dependently inhibits [3H]MK-801 binding to the PCP receptor, and that this effect is reversed by addition of glycine. Since [3H]MK-801 binding is a measure of channel activation, our results are consistent with the hypotheses that 7-Cl KYNA exerts its NMDA receptor antagonism by acting at the glycine site, and that activation of the glycine site is required for NMDA channel activity to occur.

Animals↗
PubMed1989

Interaction of [3H]MK-801 with multiple states of the N-methyl-D-aspartate receptor complex of rat brain.

N-Methyl-D-aspartate (N-Me-D-Asp) and phencyclidine receptors interactively mediate central nervous system processes including psychotomimetic effects of drugs as well as neurodegenerative, cognitive, and developmental events. To elucidate the mechanism of this interaction, effects of N-Me-D-Asp agonists and antagonists and of glycine-like agents upon binding of the radiolabeled phencyclidine receptor ligand [3H]MK-801 were determined in rat brain. Scatchard analysis revealed two discrete components of [3H]MK-801 binding after 4 hr of incubation. Incubation in the presence of L-glutamate led to an increase in apparent densities but not in affinities of both components of [3H]MK-801 binding as well as conversion of sites from apparent low to high affinity. Incubation in the presence of combined D-serine and L-glutamate led to an increase in the apparent density of high-affinity [3H]MK-801 binding compared with incubation in the presence of either L-glutamate or D-serine alone. These data support a model in which phencyclidine receptor ligands bind differentially to closed as well as open conformations of the N-Me-D-Asp receptor complex and in which glycine-like agents permit or factilitate agonist-induced conversion of N-Me-D-Asp receptors from closed to open conformations.

Animals↗
PubMed1989

Biexponential kinetics of [3H]MK-801 binding: evidence for access to closed and open N-methyl-D-aspartate receptor channels.

The phencyclidine (PCP) receptor is a site within the ion channel gated by the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. In the present study, kinetics of association and dissociation of the specific PCP receptor ligand [3H]MK-801 were determined in order to elucidate the mechanism of functioning of the NMDA receptor complex. Two distinct components of [3H]MK-801 association with apparent t1/2 values of approximately 10 min and 3 hr were resolved. Incubation with the NMDA receptor agonist L-glutamate increased the total steady state binding of [3H]MK-801 and increased the relative percentage of [3H]MK-801 binding that manifested fast rather than slow kinetics, without altering the observed rate constant of either the fast or slow component of association. The competitive NMDA receptor antagonist D(-)-2-amino-5-phosphonovaleric acid decreased total steady state binding of [3H]MK-801. These data support a model in which [3H]MK-801 can gain access to its binding site via two distinct paths, a fast hydrophilic path associated with a conformation of the NMDA receptor in which the channel is open and a slow hydrophobic path independent of the open channel. In the presence of L-glutamate, incubation with glycine increased the relative percentage of [3H]MK-801 binding that manifested fast rather than slow kinetics. The Hill coefficient for stimulation of specific [3H]MK-801 binding by L-glutamate was significantly greater than unity in either the absence or presence of glycine. Our data support a model of NMDA receptor functioning in which two molecules of agonist are required to convert the receptor complex to a conformation that is in equilibrium with the open conformation and in which glycine regulates the percentage of NMDA receptor complexes bound to two molecules of agonist that convert to the open configuration.

2-Amino-5-phosphonovalerate↗
PubMed1988

The possible role of dopamine autoreceptors in neuroleptic atypicality.

Different brain pathways have been shown to subserve the therapeutic effects of neuroleptics and their extrapyramidal side effects. Agents which can discriminate between these pathways, therefore, might be able to produce 'atypical' clinical effects. Molindone, a novel neuroleptic of the indoleamine class, has been shown in basic paradigms to discriminate between brain dopaminergic systems by virtue of its ability to preferentially inhibit dopamine autoreceptors (DARs). Clinical studies suggest that molindone may be less likely than traditional neuroleptics to induce tardive dyskinesia and that molindone may preferentially ameliorate some negative schizophrenic symptoms. We suggest that the distinct clinical effects of molindone result from its ability to block DARs.

Animals↗
PubMed1987

Non-competitive regulation of phencyclidine/sigma-receptors by the N-methyl-D-aspartate receptor antagonist D-(-)-2-amino-5-phosphonovaleric acid.

D-(-)-2-Amino-5-phosphonovaleric acid (D(-)AP5), a selective, potent competitive antagonist of N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptors was used to investigate the relationship between NMDA receptors and phencyclidine (PCP) binding. Incubation of rat brain membranes with D(-)AP5 decreased the apparent number of PCP/sigma-receptors in dose-dependent fashion without affecting their affinity for [2-thienyl-3H]cyclohexylpiperidine (TCP). These data, taken together with electrophysiological evidence that PCP non-competitively antagonizes NMDA receptor-mediated transmission, are consistent with the hypothesis that the PCP/sigma-receptor may be situated in or near a channel regulated by an NMDA receptor complex.

2-Amino-5-phosphonovalerate↗
PubMed1987

Negative schizophrenic symptomatology and the PCP (phencyclidine) model of schizophrenia.

Amphetamine induced psychosis has for the past 30 years provided a useful model for the study of schizophrenia. The amphetamine model, however, has been shown to have a number of shortcomings including an inability to model the deficit symptoms of schizophrenia. PCP (phencyclidine) has been shown to be capable of inducing a schizophreniform psychosis consisting of both productive and defict symptomatology. PCP induced psychosis, therefore, may provide a useful model of schizophrenia. This paper reviews the literature concerning the PCP model of schizophrenia and provides some independent confirmation of the ability of PCP to modulate mesocortical dopaminergic activity. Since PCP appears to mediate its CNS effects via a subclass of glutamate receptors, a possible glutamate theory of schizophrenia is proposed.

Animals↗
PubMedDate not supplied

Cellular generators of the cortical auditory evoked potential initial component.

Cellular generators of the initial cortical auditory evoked potential (AEP) component were determined by analyzing laminar profiles of click-evoked AEPs, current source density, and multiple unit activity (MUA) in primary auditory cortex of awake monkeys. The initial AEP component is a surface-negative wave, N8, that peaks at 8-9 msec and inverts in polarity below lamina 4. N8 is generated by a lamina 4 current sink and a deeper current source. Simultaneous MUA is present from lower lamina 3 to the subjacent white matter. Findings indicate that thalamocortical afferents are a generator of N8 and support a role for lamina 4 stellate cells. Relationships to the human AEP are discussed.

Acoustic Stimulation↗
PubMedDate not supplied

Intracortical mechanisms of mismatch negativity dysfunction in schizophrenia.

Event-related potentials provide an objective index of neurocognitive dysfunction in schizophrenia. Schizophrenia subjects show a decreased mismatch negativity (MMN) amplitude relative to age- and sex-matched controls, along with a characteristic pattern of MMN dysfunction across conditions. Deficits in MMN generation are accompanied by (1) impaired precision of auditory sensory memory performance and (2) an interstimulus-interval-dependent deficit in auditory N(1) generation. Similar deficits are observed following systemic or local infusion of N-methyl-D-aspartate (NMDA) antagonists, supporting glutamatergic and phencyclidine/NMDA models of the disorder. Deficits in MMN generation may also be seen following focal cortical damage, especially to the dorsolateral prefrontal cortex. MMN thus provides a useful tool for investigating mechanisms underlying brain dysfunction in schizophrenia.

Attention↗