Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors

Rafal T. Olszewski, Marta M. Wegorzewska, Ana C. Monteiro, Kristyn A. Krolikowski, Jia Zhou, Alan P. Kozikowski, Katrice Long, John Mastropaolo, Stephen I. Deutsch, Joseph H. Neale

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Background: N-methyl-d-aspartate (NMDA) receptor open channel blockers phencyclidine (PCP) and dizocilpine (MK-801) elicit schizophrenia-like symptoms in humans and in animal models. Group II metabotropic glutamate receptor agonists reverse the behavioral effects of PCP and MK-801 in animal models. N-acetylaspartylglutamate (NAAG), the third most prevalent neurotransmitter in the mammalian nervous system, is a selective group II metabotropic glutamate receptor agonist. We previously reported that ZJ43, a potent inhibitor of the enzymes that inactivate synaptically released NAAG, reduced motor and stereotypic effects of PCP in the rat. Methods: To confirm the efficacy of NAAG peptidase inhibition in decreasing motor behaviors induced by PCP and MK-801, ZJ43 was tested in additional schizophrenia models. Results: ZJ43 reduced MK-801-induced motor activation in a mouse model that has been used to characterize the efficacy of a wide range of pharmacotherapies for this human disorder. In a second mouse strain, the peptidase inhibitor reduced PCP-induced stereotypic movements. ZJ43 also reduced PCP-induced negative symptoms in a resident-intruder assay. The group II metabotropic glutamate receptor antagonist, LY341495, blocked the effect of NAAG peptidase inhibition in these mouse models of positive and negative PCP- and MK-801-induced behaviors. Additionally, LY341495 alone increased some PCP-induced behaviors suggesting that normal levels of NAAG act to moderate the effect of PCP via a group II mGluR. Conclusions: These data support the proposal that NAAG peptidase inhibition and elevation of synaptic NAAG levels represent a new therapeutic approach to treating the positive and negative symptoms of schizophrenia that are modeled by open channel NMDA receptor antagonists.

Original languageEnglish (US)
Pages (from-to)86-91
Number of pages6
JournalBiological Psychiatry
Volume63
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

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Glutamate Carboxypeptidase II
Phencyclidine
Metabotropic Glutamate Receptors
Dizocilpine Maleate
LY 341495
Excitatory Amino Acid Agonists
Schizophrenia
Animal Models
Excitatory Amino Acid Antagonists
Enzyme Inhibitors
Protease Inhibitors
Nervous System
Neurotransmitter Agents
Inhibition (Psychology)
Drug Therapy
N-acetyl-1-aspartylglutamic acid
ZJ43

Keywords

  • Group II metabotropic glutamate receptor
  • LY341495
  • mGluR3
  • MK-801
  • N-acetylaspartylglutamate
  • NAAG
  • NMDA receptors
  • phencyclidine
  • schizophrenia

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors. / Olszewski, Rafal T.; Wegorzewska, Marta M.; Monteiro, Ana C.; Krolikowski, Kristyn A.; Zhou, Jia; Kozikowski, Alan P.; Long, Katrice; Mastropaolo, John; Deutsch, Stephen I.; Neale, Joseph H.

In: Biological Psychiatry, Vol. 63, No. 1, 01.01.2008, p. 86-91.

Research output: Contribution to journalArticle

Olszewski, RT, Wegorzewska, MM, Monteiro, AC, Krolikowski, KA, Zhou, J, Kozikowski, AP, Long, K, Mastropaolo, J, Deutsch, SI & Neale, JH 2008, 'Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors', Biological Psychiatry, vol. 63, no. 1, pp. 86-91. https://doi.org/10.1016/j.biopsych.2007.04.016
Olszewski, Rafal T. ; Wegorzewska, Marta M. ; Monteiro, Ana C. ; Krolikowski, Kristyn A. ; Zhou, Jia ; Kozikowski, Alan P. ; Long, Katrice ; Mastropaolo, John ; Deutsch, Stephen I. ; Neale, Joseph H. / Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors. In: Biological Psychiatry. 2008 ; Vol. 63, No. 1. pp. 86-91.
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