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NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR
Author(s) -
Olszewski Rafal T.,
Bukhari Noreen,
Zhou Jia,
Kozikowski Alan P.,
Wroblewski Jarda T.,
ShamimiNoori Susan,
Wroblewska Barbara,
Bzdega Tomasz,
Vicini Stefano,
Barton Franca B.,
Neale Joseph H.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02358.x
Subject(s) - metabotropic glutamate receptor , phencyclidine , glutamate carboxypeptidase ii , glutamate receptor , metabotropic receptor , metabotropic glutamate receptor 1 , agonist , nmda receptor , neuroscience , metabotropic glutamate receptor 2 , pharmacology , metabotropic glutamate receptor 5 , metabotropic glutamate receptor 7 , chemistry , psychology , receptor , medicine , biology , biochemistry , prostate , cancer
Phencyclidine (PCP) administration elicits positive and negative symptoms that resemble those of schizophrenia and is widely accepted as a model for the study of this human disorder. Group II metabotropic glutamate receptor (mGluR) agonists have been reported to reduce the behavioral and neurochemical effects of PCP. The peptide neurotransmitter, N‐acetylaspartylglutamate (NAAG), is a selective group II agonist. We synthesized and characterized a urea‐based NAAG analogue, ZJ43. This novel compound is a potent inhibitor of enzymes, glutamate carboxypeptidase II ( K i = 0.8 n m ) and III ( K i = 23 n m ) that deactivate NAAG following synaptic release. ZJ43 (100 µ m ) does not directly interact with NMDA receptors or metabotropic glutamate receptors. Administration of ZJ43 significantly reduced PCP‐induced motor activation, falling while walking, stereotypic circling behavior, and head movements. To test the hypothesis that this effect of ZJ43 was mediated by increasing the activation of mGluR3 via increased levels of extracellular NAAG, the group II mGluR selective antagonist LY341495 was co‐administered with ZJ43 prior to PCP treatment. This antagonist completely reversed the effects of ZJ43. Additionally, LY341495 alone increased PCP‐induced motor activity and head movements suggesting that normal levels of NAAG act to moderate the effect of PCP on motor activation via a group II mGluR. These data support the view that NAAG peptidase inhibitors may represent a new therapeutic approach to some of the components of schizophrenia that are modeled by PCP.