Phencyclidine (PCP) is a major clinical psychotogenic agent and drug of abuse. PCP and other dissociative anesthetics induce their unique behavioral effects by blocking neurotransmission mediated at the N-methyl-D-aspartate (NMDA)-type glutamate receptor. In addition to the main agonist-binding site for glutamate, the NMDA receptor complex contains multiple co-agonist/modulatory sites, including a strychnine-insensitive glycine-binding site. In rodents, stimulation of the glycine site reverses PCP-induced hyperactivity, whereas in humans glycine and similar agents (e.g., D-serine, D-cyCloserine) ameliorate PCP psychosis-like symptoms of schizophrenia. In CNS glycine levels in the immediate vicinity of NMDA receptors are maintained at low, subsaturating doses by the action of colocalized glycine transporters. Therefore, inhibition of glycine uptake, rather than administration of large doses of glycine, may be a preferred method for elevating glycine levels in the immediate vicinity of NMDA receptors. This is an application for continuation of a project initiated in 1982 to investigate mechanisms underlying PCP induced psychosis. This cycle of the project with investigate effects of subchronic PCP administration in animal models of schizophrenia. Specific measures to be studied include: 1. PCP-induced potentiation of amphetamine-stimulated dopamine release in prefrontal cortex and striatum; 2. PCP-induced disruption of prepulse inhibition and neurophysiological deficits, similar to those observed in schizophrenia; and 3. PCP-induced behavioral deficits in social interaction models. Projects will also continue ongoing investigations into effectiveness of glycinergic agents, including glycine site agonists (e.g.. glycine, D-serine) and glycine transport inhibitors (GTIs) in reversing PCP-induced behavioral, neurochemical and neurophysiological deficits in animals. Effects of glycinergic agents will be compared to those of typical/atypical antipsychotics. The overall goals of the project are 1) to evaluate the potential utility of glycine agonists/GTIs in the treatment of PCP psychosis and PCP psychosis-like symptoms of schizophrenia, and 2) to develop animal models sensitive to the non-dopaminergic, as well as dopaminergic, consequences of PCP-induced NMDA receptor blockade.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA003383-17
Application #
6401985
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Frankenheim, Jerry
Project Start
1982-07-01
Project End
2006-05-31
Budget Start
2001-08-01
Budget End
2002-05-31
Support Year
17
Fiscal Year
2001
Total Cost
$323,829
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
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Kantrowitz, Joshua; Javitt, Daniel C (2012) Glutamatergic transmission in schizophrenia: from basic research to clinical practice. Curr Opin Psychiatry 25:96-102
Moghaddam, Bita; Javitt, Daniel (2012) From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology 37:4-15
Javitt, Daniel C; Zukin, Stephen R; Heresco-Levy, Uriel et al. (2012) Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull 38:958-66
Balla, Andrea; Schneider, Samantha; Sershen, Henry et al. (2012) Effects of novel, high affinity glycine transport inhibitors on frontostriatal dopamine release in a rodent model of schizophrenia. Eur Neuropsychopharmacol 22:902-10
Javitt, Daniel C; Schoepp, Darryle; Kalivas, Peter W et al. (2011) Translating glutamate: from pathophysiology to treatment. Sci Transl Med 3:102mr2

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