Orally active glutamate carboxypeptidase II inhibitor 2-MPPA attenuates dizocilpine-induced prepulse inhibition deficits in mice

Yuto Takatsu, Yuko Fujita, Takashi Tsukamoto, Barbara S. Slusher, Kenji Hashimoto

Research output: Contribution to journalArticle

Abstract

Glutamate carboxypeptidase II (GCP II) is a glial enzyme responsible for the hydrolysis of N-acetylaspartylglutamate (NAAG) into glutamate and N-acetylaspartate (NAA). Abnormalities in glutamate neurotransmission are implicated in the pathophysiology of schizophrenia. In this study, we examined the effects of a novel, orally active GCP II inhibitor, 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA), on the prepulse inhibition (PPI) deficits after administration of the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine. Oral administration of 2-MPPA (10, 30 or 100 mg/kg) significantly attenuated dizocilpine (0.1 mg/kg)-induced PPI deficits in mice, in a dose dependent manner. Furthermore, the efficacy of 2-MPPA on dizocilpine-induced PPI deficits was significantly antagonized by pretreatment with the selective group II metabotropic glutamate receptor (mGluR) antagonist LY341495 (1.0 mg/kg). In the same model, however, the selective group II mGluR agonist LY354740 (3, 10 or 30 mg/kg) significantly attenuated dizocilpine-induced PPI deficits at only one dose and prepulse intensity. Our findings suggest that GCP II inhibition may be useful therapeutic strategy for schizophrenia. From a mechanistic perspective, while increased NAAG and activation of group II mGluRs may contribute to the therapeutic efficacy of 2-MPPA, it is likely that additional pharmacological activities are also involved.

Original languageEnglish (US)
Pages (from-to)82-86
Number of pages5
JournalBrain research
Volume1371
DOIs
StatePublished - Jan 31 2011

Keywords

  • Glutamate
  • Glutamate carboxypeptidase II
  • Metabotropic glutamate receptor
  • NAAG
  • NMDA receptors

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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