NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR

Rafal T. Olszewski, Noreen Bukhari, Jia Zhou, Alan P. Kozikowski, Jarda T. Wroblewski, Susan Shamimi-Noori, Barbara Wroblewska, Tomasz Bzdega, Stefano Vicini, Franca B. Barton, Joseph H. Neale

Research output: Contribution to journalArticle

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Abstract

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 (Ki = 0.8 nM) and III (Ki = 23 nM) that deactivate NAAG following synaptic release. ZJ43 (100 μM) 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.

Original languageEnglish (US)
Pages (from-to)876-885
Number of pages10
JournalJournal of Neurochemistry
Volume89
Issue number4
DOIs
StatePublished - May 2004
Externally publishedYes

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Glutamate Carboxypeptidase II
Metabotropic Glutamate Receptors
Locomotion
Schizophrenia
LY 341495
Head Movements
Chemical activation
Accidental Falls
Excitatory Amino Acid Agonists
Phencyclidine
Excitatory Amino Acid Antagonists
Enzyme Inhibitors
Protease Inhibitors
N-Methyl-D-Aspartate Receptors
Walking
Neurotransmitter Agents
Urea
Inhibition (Psychology)
ZJ43
Motor Activity

Keywords

  • mGluR3
  • N-acetylaspartylglutamate
  • NMDA receptors
  • Phencyclidine
  • Schizophrenia

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. / Olszewski, Rafal T.; Bukhari, Noreen; Zhou, Jia; Kozikowski, Alan P.; Wroblewski, Jarda T.; Shamimi-Noori, Susan; Wroblewska, Barbara; Bzdega, Tomasz; Vicini, Stefano; Barton, Franca B.; Neale, Joseph H.

In: Journal of Neurochemistry, Vol. 89, No. 4, 05.2004, p. 876-885.

Research output: Contribution to journalArticle

Olszewski, RT, Bukhari, N, Zhou, J, Kozikowski, AP, Wroblewski, JT, Shamimi-Noori, S, Wroblewska, B, Bzdega, T, Vicini, S, Barton, FB & Neale, JH 2004, 'NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR', Journal of Neurochemistry, vol. 89, no. 4, pp. 876-885. https://doi.org/10.1111/j.1471-4159.2004.02358.x
Olszewski, Rafal T. ; Bukhari, Noreen ; Zhou, Jia ; Kozikowski, Alan P. ; Wroblewski, Jarda T. ; Shamimi-Noori, Susan ; Wroblewska, Barbara ; Bzdega, Tomasz ; Vicini, Stefano ; Barton, Franca B. ; Neale, Joseph H. / NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. In: Journal of Neurochemistry. 2004 ; Vol. 89, No. 4. pp. 876-885.
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AU - Zhou, Jia

AU - Kozikowski, Alan P.

AU - Wroblewski, Jarda T.

AU - Shamimi-Noori, Susan

AU - Wroblewska, Barbara

AU - Bzdega, Tomasz

AU - Vicini, Stefano

AU - Barton, Franca B.

AU - Neale, Joseph H.

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