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Biomedical subjects

D C Javitt

Publications and source records attributed to D C Javitt.

At least 73 records · Page 4Linked to original sources
PubMed1996

Glycinergic augmentation of NMDA receptor-mediated neurotransmission in the treatment of schizophrenia.

Phencyclidine (PCP) induces a psychotic state closely resembling schizophrenia in normal individuals. PCP and related agents induce their unique behavioral effects by blocking neurotransmission mediated at N-methyl-D-aspartate (NMDA)-type glutamate receptors, indicating that dysfunction of NMDA receptor-mediated neurotransmission may play a crucial role in the pathophysiology of schizophrenia. NMDA receptors are activated by the amino acids glutamate and glycine, working at independent binding sites. Glutamate cannot be administered exogenously because of excitotoxicity. In contrast, glycine administered exogenously may potentiate NMDA receptor-mediated neurotransmission in vivo following peripheral administration. In rodents, glycine is effective in elevating brain glycine levels and reversing PCP-induced hyperactivity at doses of 0.8 g/kg and above. Three studies have now been completed utilizing moderate to high (0.4-0.8 g/kg/day) doses of glycine, added to neuroleptics, for the treatment of schizophrenia. Across studies, 15 to 30 percent improvement in negative symptoms was observed with no corresponding worsening of positive symptoms. Although preliminary, these studies indicate that dietary supplementation with glycine or treatment with other glycinergic agents may be effective in the treatment of schizophrenia.

Adult↗
PubMed1995

Impaired mismatch negativity generation reflects widespread dysfunction of working memory in schizophrenia.

BACKGROUND: Impaired P300 (P3) generation is one of the most robust indices of brain dysfunction in schizophrenia. This study investigates the integrity of cognitive event-related potentials that precede P3 in an "oddball" paradigm to determine the earliest stages at which auditory information processing is impaired in schizophrenia. METHODS: Cognitive event-related potential components including mismatch negativity (MMN), N2, and P3 were recorded from subjects with chronic schizophrenia who were receiving medication (n = 20), from those who were withdrawn from drug treatment (n = 11), and from healthy volunteers (n = 11) during an auditory oddball paradigm. Recordings were made in both passive and active response conditions. The MMN, N2, and P3 amplitudes were compared across groups and the degree of MMN deficit was correlated with the degree of P3 reduction as a function of diagnostic group. RESULTS: Schizophrenic subjects showed severe impairments in the generation of MMN and N2 as well as P3. Across groups, the decrement in MMN amplitude correlated significantly with the decrement in P3 amplitude. There were no significant between-group differences in MMN topography. CONCLUSIONS: The present study demonstrates that the neurophysiological deficits associated with schizophrenia, as reflected in cognitive event-related potential generation, are pervasive, extending even to the level of the sensory cortex. Mismatch negativity indexes the functioning of an automatic alerting mechanism designed to stimulate individuals to explore unexpected environmental events. Dysfunction of this mechanism may contribute to the deficit state associated with schizophrenia.

Adult↗
PubMed1995

The mismatch negativity of event-related potentials as a probe of transient auditory memory: a review.

The use of the mismatch negativity as a probe to study the memory upon which it depends is reviewed. Topics about the memory include its duration, its capacity, the kind of information that can be stored in the memory, how the information is stored, whether the memory is accessed in parallel or in series, whether it is hard-wired or can be modified by experience, and its relationship to sensory memory.

Evoked Potentials, Auditory↗
PubMed1995

Auditory sensory ("echoic") memory dysfunction in schizophrenia.

OBJECTIVE: Studies of working memory dysfunction in schizophrenia have focused largely on prefrontal components. This study investigated the integrity of auditory sensory ("echoic") memory, a component that shows little dependence on prefrontal functioning. METHOD: Echoic memory was investigated in 20 schizophrenic subjects and 20 age- and IQ-matched normal comparison subjects with the use of nondelayed and delayed tone matching. RESULTS: Schizophrenic subjects were markedly impaired in their ability to match two tones after an extremely brief delay between them (300 msec) but were unimpaired when there was no delay between tones. CONCLUSIONS: Working memory dysfunction in schizophrenia affects brain regions outside the prefrontal cortex as well as within.

Acoustic Stimulation↗
PubMed1994

Detection of stimulus deviance within primate primary auditory cortex: intracortical mechanisms of mismatch negativity (MMN) generation.

Mismatch negativity (MMN) is a cognitive, auditory event-related potential (AEP) that reflects preattentive detection of stimulus deviance and indexes the operation of the auditory sensory ('echoic') memory system. MMN is elicited most commonly in an auditory oddball paradigm in which a sequence of repetitive standard stimuli is interrupted infrequently and unexpectedly by a physically deviant 'oddball' stimulus. Electro- and magnetoencephalographic dipole mapping studies have localized the generators of MMN to supratemporal auditory cortex in the vicinity of Heschl's gyrus, but have not determined the degree to which MMN reflects activation within primary auditory cortex (AI) itself. The present study, using moveable multichannel electrodes inserted acutely into superior temporal plane, demonstrates a significant contribution of AI to scalp-recorded MMN in the monkey, as reflected by greater response of AI to loud or soft clicks presented as deviants than to the same stimuli presented as repetitive standards. The MMN-like activity was localized primarily to supragranular laminae within AI. Thus, standard and deviant stimuli elicited similar degrees of initial, thalamocortical excitation. In contrast, responses within supragranular cortex were significantly larger to deviant stimuli than to standards. No MMN-like activity was detected in a limited number to passes that penetrated anterior and medial to AI. AI plays a well established role in the decoding of the acoustic properties of individual stimuli. The present study demonstrates that primary auditory cortex also plays an important role in processing the relationships between stimuli, and thus participates in cognitive, as well as purely sensory, processing of auditory information.

Acoustic Stimulation↗
PubMed1994

Amelioration of negative symptoms in schizophrenia by glycine.

Phencyclidine induces a psychotomimetic state by blocking neurotransmission at N-methyl-D-aspartic acid (NMDA) receptors. In a double-blind, placebo-controlled fashion, 14 medicated patients with chronic schizophrenia were treated with glycine, a potentiator of NMDA-receptor-mediated neurotransmission. Significant improvement in negative symptoms occurred in the group given glycine but not in the group given placebo, suggesting that potentiation of NMDA-receptor-mediated neurotransmission may represent an effective treatment for neuroleptic-resistant negative symptoms in schizophrenia.

Adult↗
PubMed1994

Activation-related and activation-independent effects of polyamines on phencyclidine receptor binding within the N-methyl-D-aspartate receptor complex.

The phencyclidine (PCP) receptor is located within the N-methyl-D-aspartate (NMDA) receptor-gated ion channel. The functional state of the NMDA receptor complex thus influences parameters of radioligand binding to the PCP receptor, and PCP receptor ligands can serve as in vitro probes for elucidation of NMDA receptor activation mechanisms. PCP receptor binding is stimulated by NMDA receptor agonists such as L-glutamate and also by distinct classes of modulatory agents such as glycine-like amino acids and polyamines such as spermidine (SPD). The present study utilizes a kinetic approach permitting differentiation of PCP receptor binding within closed and activated conformations of the NMDA receptor complex. The results demonstrate that SPD increases radioligand binding to the PCP receptor through two distinct mechanisms. First, SPD, like glycine, increases the percentage of time that NMDA channels remain in the open state in the presence of L-glutamate, consistent with a role as a positive allosteric modulator of NMDA receptor activation. Second, unlike glycine, SPD increases the affinity of the PCP receptor for its ligands. The latter effect does not appear to reflect increased NMDA receptor activation. SPD does not induce glycine-like alteration of the EC50 value for stimulation of PCP receptor binding by L-glutamate, suggesting that the effects of SPD cannot be attributed solely to augmentation of glycine binding. These findings demonstrate first that total specific PCP receptor binding cannot, of itself, be used as an index of NMDA receptor activation and second, glycine and polyamines differ in the mechanisms by which they potentiate PCP receptor binding.

Animals↗
PubMed1993

Impairment of early cortical processing in schizophrenia: an event-related potential confirmation study.

Abnormalities of auditory information processing represent a core feature of schizophrenic psychopathology. Event-related potentials (ERP) provide an objective index of the information processing deficits associated with schizophrenia and a tool for investigation of the underlying pathophysiology. The best established abnormality is a decrease in the amplitude of auditory P300. In an "oddball" paradigm, P300 is preceded by a series of earlier, negative-polarity ERP components that index discrete, prior information-processing events. The earliest such component, mismatch negativity (MMN), is elicited whenever a deviant, "oddball" stimulus interrupts a sequence of repetitive standard stimuli. MMN is generated principally within primary auditory cortex or adjacent structures on the superior temporal plane, suggesting that it indexes the earliest cortical event in the cognitive processing of auditory information. In the present study, MMN was studied in a group of 14 chronic schizophrenic subjects relative to 12 age- and IQ-matched normal controls in a passive auditory oddball paradigm in order to test the hypothesis that auditory information processing is impaired in schizophrenia, even at the level of primary sensory cortex. Schizophrenic subjects showed a significant reduction in MMN amplitude relative to controls, with a trend toward a greater deficit on the left than the right side. The finding of impaired MMN generation in schizophrenia suggests that information processing is impaired even at the level of auditory cortex and that the pathophysiological processes underlying information processing dysfunction in schizophrenia are widespread throughout the cortex, rather than limited to high-order association cortex such as prefrontal or mesial temporal cortex.

Adult↗
PubMed1993

Mismatch negativity in hyperactive children: effects of methylphenidate.

This pilot study investigates electrophysiological correlates of methylphenidate (MP) treatment among hyperkinetic children who are clinical responders to therapy. Event-related potentials were obtained from a small sample (6 hyperactive and 5 controls) during an auditory "oddball" task. In the ignore condition, oddball tones elicited a frontocentral "mismatch" negativity (MMN) during the 100- to 200-msec latency range following stimulus presentation. In the attend condition, oddball target tones elicited a centroparietal P3 as well. MP significantly decreased hyperkinetic behaviors. Preliminary analyses of the electrophysiological data indicated a decreased amplitude of the P3 waveform among hyperkinetic children and a trend toward normalization on MP. Waveform abnormalities in the latency range of control MMN suggested either a decrease in MMN amplitude or an increase in MMN latency in hyperactive subjects along with a trend toward normalization by MP. The preliminary data are suggestive of information-processing abnormalities among hyperactive children that may be sensitive to MP therapy.

Attention Deficit Disorder with Hyperactivity↗
PubMed1992

Demonstration of mismatch negativity in the monkey.

In humans, deviant auditory stimuli elicit an event-related potential (ERP) component, termed "mismatch negativity" (MMN), that reflects the operation of a cortical detector of infrequent stimulus change. Epidural auditory ERPs were recorded from 3 cynomolgous monkeys in response to soft and loud clicks. "Oddball" loud or soft stimuli elicited a long-duration frontocentral negativity, peaking at approximately 85 msec, that was superimposed upon cortically generated obligatory ERP components. These data suggest that monkeys might serve as a heuristically valuable system in which to study the neurochemical and neuroanatomical substrates of early context-dependent ERP generation.

Acoustic Stimulation↗
PubMed1991

Polyamine effects upon N-methyl-D-aspartate receptor functioning: differential alteration by glutamate and glycine site antagonists.

Polyamines such as spermidine potentiate activation of the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. The goal of the present study was to investigate interactions between the putative polyamine binding site and previously described sites for glutamate and glycine. Binding of the high-potency PCP receptor ligand [3H]MK-801 to well-washed rat brain membranes was used as an in vitro probe of NMDA receptor activation. Spermidine concentration-response studies were performed in the absence and presence of both glutamate and glycine, with and without D-(-)-2-amino-5-phosphonovaleric acid (D(-)-AP-5) or 7-chlorokynurenic acid (7Cl-KYN). Incubation in the presence of spermidine alone induced a 20.4-fold increase in [3H]MK-801 binding with an EC50 value of 13.3 microM. The mean concentration of spermidine which induced maximal stimulation of binding was 130 microM (n = 10, S.E.M. = 24.66, range = 25-250 microM). Glutamate (10 microM) decreased the EC50 value for spermidine-induced stimulation of [3H]MK-801 binding to 3.4 microM. Glycine (10 microM) did not significantly alter either maximum spermidine-induced [3H]MK-801 binding or the EC50 value for spermidine-induced stimulation of [3H]MK-801 binding. Incubation in the presence of the specific glutamate antagonist D(-)AP-5 attenuated [3H]MK-801 binding in a glutamate-reversible fashion. The competitive glycine antagonist 7Cl-KYN decreased maximum spermidine-induced [3H]MK-801 binding in a glycine-reversible fashion. In addition, 7Cl-KYN increased the EC50 value for spermidine-induced stimulation of [3H]MK-801 binding while D(-)AP-5 was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1991

Recent advances in the phencyclidine model of schizophrenia.

OBJECTIVE: Phencyclidine (PCP, "angel dust") induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding of schizophrenic pathophysiology. METHOD: Twenty-five papers were identified that described the clinical dose and serum and CSF levels at which PCP induces its psychotomimetic effects. The dose range of PCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. RESULTS: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation of its receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. CONCLUSIONS: These findings suggest that endogenous dysfunction of NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models of schizophrenia are discussed in relationship to the diagnosis and etiology of schizophrenia.

Animals↗