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 ameliorates 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 will utilize information gained during previous cycles to determine the effectiveness of glycine site agonists and uptake antagonists in reversing specific behavioral and physiological effects of PCP in rodents and primates. Characteristics of specific glycine site agonists (e.g., glycine, D-serine) and glycine uptake antagonists (e.g., glycyldodecylamide) will be evaluated in rat brain homogenate. Effects of these drugs will then be evaluated relative to PCP-induced hyperactivity in rodents and PCP-induced social withdrawal and psychophysiological dysfunction in monkeys. The overall goals of the project are (1) to evaluate the likely specific usefulness of glycine site agonists/glycine uptake antagonists 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 #
2R01DA003383-14A2
Application #
2698613
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Frankenheim, Jerry
Project Start
1982-07-01
Project End
2001-07-31
Budget Start
1998-09-30
Budget End
1999-07-31
Support Year
14
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
Kantrowitz, Joshua T; Hoptman, Matthew J; Leitman, David I et al. (2015) Neural Substrates of Auditory Emotion Recognition Deficits in Schizophrenia. J Neurosci 35:14909-21
Kantrowitz, J T; Scaramello, N; Jakubovitz, A et al. (2014) Amusia and protolanguage impairments in schizophrenia. Psychol Med 44:2739-48
Kantrowitz, J T; Hoptman, M J; Leitman, D I et al. (2014) The 5% difference: early sensory processing predicts sarcasm perception in schizophrenia and schizo-affective disorder. Psychol Med 44:25-36
Guilfoyle, David N; Gerum, Scott V; Sanchez, Jamie L et al. (2013) Functional connectivity fMRI in mouse brain at 7T using isoflurane. J Neurosci Methods 214:144-8
Javitt, Daniel C (2012) Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol :367-99
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

Showing the most recent 10 out of 61 publications