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The peptide neurotransmitter, N\u2010acetylaspartylglutamate (NAAG), is a selective group II agonist. We synthesized and characterized a urea\u2010based NAAG analogue, ZJ43. This novel compound is a potent inhibitor of enzymes, glutamate carboxypeptidase II (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u2003=\u20030.8\u2003n<jats:sc>m<\/jats:sc>) and III (<jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub>\u2003=\u200323\u2003n<jats:sc>m<\/jats:sc>) that deactivate NAAG following synaptic release. ZJ43 (100\u2003\u00b5<jats:sc>m<\/jats:sc>) does not directly interact with NMDA receptors or metabotropic glutamate receptors. Administration of ZJ43 significantly reduced PCP\u2010induced 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\u2010administered with ZJ43 prior to PCP treatment. This antagonist completely reversed the effects of ZJ43. Additionally, LY341495 alone increased PCP\u2010induced 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.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2004.02358.x","type":"journal-article","created":{"date-parts":[[2006,3,3]],"date-time":"2006-03-03T12:15:48Z","timestamp":1141388148000},"page":"876-885","source":"Crossref","is-referenced-by-count":128,"title":["NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR"],"prefix":"10.1111","volume":"89","author":[{"given":"Rafal T.","family":"Olszewski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noreen","family":"Bukhari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan P.","family":"Kozikowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarda T.","family":"Wroblewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Shamimi\u2010Noori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Wroblewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Bzdega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Vicini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franca B.","family":"Barton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph H.","family":"Neale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,4,13]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.01117.x"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(97)00531-9"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02361.x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0893-133X(88)90012-7"},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0022-3565(24)35084-0","article-title":"The metabotropic glutamate 2\/3 receptor agonists LY354740 and LY379268 selectively attenuate phencyclidine versus d\u2010amphetamine motor behaviors in rats","volume":"291","author":"Cartmell J.","year":"1999","journal-title":"J. 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