Phencyclidine (PCP) induces a psychotic state that closely resembles schizophrenia by blocking neurotransmission at the NMDA-type glutamate receptor. The ability of NMDA antagonists to induce schizophrenia-like symptoms indicates that endogenous NMDA receptor dysfunction or dysregulation may contribute substantially to the pathophysiology of schizophrenia. This K02 award will enable the candidate to pursue investigations directed to the continued development of the PCP/NMDA model of schizophrenia. Specific projects will include: 1) characterization of neurophysiological and neurocognitive dysfunction in schizophrenia relative to the predictions of the PCP/NMDA model, 2) investigation of mechanisms underlying neurophysiological and neurocognitive dysfunction in schizophrenia using multichannel intracortical recordings in monkeys, 3) determination of the effects of NMDA augmenting agents on negative symptoms and cognitive functioning in schizophrenia, and 4) development of novel, clinically relevant NMDA augmentation strategies. Neurophysiological studies will focus on impaired generation of mismatch negativity (MMN) and other cognitive event-related potential (ERP) in schizophrenia. Treatment studies will focus on the clinical use of glycine and characterization of preclinical effects of glycine precursors and/or reuptake inhibitors on rodent behavior and free extracellular glycine levels. The research will build upon studies currently supported by NIH research and career development awards to the candidate. Over the past several years, the candidate has acquired expertise in PCP/NMDA neuropharmacology and in the application neurophysiological methods to the analysis of brain dysfunction in schizophrenia, and has gained experience in clinical psychopharmacology research in schizophrenia. This award will permit the candidate to develop further expertise in neurophysiology and psychopharmacology and to obtain exposure and experience in the use of structural and functional neuroimaging in schizophrenia.
| Butler, Pamela D; Schechter, Isaac; Revheim, Nadine et al. (2010) Has an important test been overlooked? Closure flexibility in schizophrenia. Schizophr Res 118:20-5 |
| Leitman, David I; Laukka, Petri; Juslin, Patrik N et al. (2010) Getting the cue: sensory contributions to auditory emotion recognition impairments in schizophrenia. Schizophr Bull 36:545-56 |
| Leitman, David I; Sehatpour, Pejman; Shpaner, Marina et al. (2009) Mismatch negativity to tonal contours suggests preattentive perception of prosodic content. Brain Imaging Behav 3:284-91 |
| Butler, Pamela D; Tambini, Arielle; Yovel, Galit et al. (2008) What's in a face? Effects of stimulus duration and inversion on face processing in schizophrenia. Schizophr Res 103:283-92 |
| Javitt, Daniel C; Spencer, Kevin M; Thaker, Gunvant K et al. (2008) Neurophysiological biomarkers for drug development in schizophrenia. Nat Rev Drug Discov 7:68-83 |
| Javitt, Daniel C (2008) Phenomenology, aetiology and treatment of schizophrenia. Novartis Found Symp 289:4-16;discussion 17-22, 87-93 |
| Kurylo, Daniel D; Pasternak, Roey; Silipo, Gail et al. (2007) Perceptual organization by proximity and similarity in schizophrenia. Schizophr Res 95:205-14 |
| Javitt, Daniel C; Rabinowicz, Esther; Silipo, Gail et al. (2007) Encoding vs. retention: differential effects of cue manipulation on working memory performance in schizophrenia. Schizophr Res 91:159-68 |
| Butler, Pamela D; Martinez, Antigona; Foxe, John J et al. (2007) Subcortical visual dysfunction in schizophrenia drives secondary cortical impairments. Brain 130:417-30 |
| Linn, Gary S; O'Keeffe, Robert T; Lifshitz, Kenneth et al. (2007) Behavioral effects of orally administered glycine in socially housed monkeys chronically treated with phencyclidine. Psychopharmacology (Berl) 192:27-38 |
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