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Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP and d-amphetamine models of schizophrenia

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Abstract

Rationale

Group II metabotropic glutamate receptor (mGluR) agonists represent a novel approach to the treatment of schizophrenia. Inasmuch as the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) activates these receptors, NAAG peptidase inhibitors conceptually represent a parallel path toward development of new antipsychotic drugs. While group II agonists are effective in several animal models of schizophrenia, they are reported to lack efficacy in moderating the effects of phencyclidine (PCP) on prepulse inhibition of acoustic startle in animal models of sensory processing deficits found in this disorder.

Objective

The objective of this study was to re-examine the efficacy of a group II metabotropic glutamate agonist and NAAG peptidase inhibitors in prepulse inhibition models of schizophrenia across two strains of mice.

Methods

The method used was an assay to determine the efficacy of these drugs in moderating the reduction in prepulse inhibition of acoustic startle in mice treated with PCP and d-amphetamine.

Results

The group II agonist LY354740 (5 and 10 mg/kg) moderated the effects of PCP on prepulse inhibition of acoustic startle in DBA/2 but not C57BL/6 mice. In contrast, two NAAG peptidase inhibitors, ZJ43 (150 mg/kg) and 2-PMPA (50, 100, and 150 mg/kg), did not significantly affect the PCP-induced reduction in prepulse inhibition in either strain.

Conclusions

These data demonstrate that the efficacy of group II agonists in this model of sensory motor processing is strain-specific in mice. The difference between the effects of the group II agonist and the peptidase inhibitors in the DBA/2 mice may relate to the difference in efficacy of NAAG and the agonist at mGluR2.

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Acknowledgment

This research was supported by NIH (R01 MH 79983) and by an endowment and generous gift from Nancy and Daniel Paduano. CPP and KAK were supported by a grant to Georgetown University (JHN) from the Howard Hughes Medical Institute through the Precollege and Undergraduate Science Education Program. We thank Jacqueline Crawley for advice on the experimental design and for reviewing a draft of this manuscript. The authors have no financial relationships with the sponsors of this research. Experiments comply with the current laws of the United States.

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  1. Department of Biology, Georgetown University, 37th and O Sts., NW, Washington, DC, 20057, USA

    Caterina P. Profaci, Kristyn A. Krolikowski, Rafal T. Olszewski & Joseph H. Neale

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  1. Caterina P. Profaci
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  2. Kristyn A. Krolikowski
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  3. Rafal T. Olszewski
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  4. Joseph H. Neale
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Correspondence to Joseph H. Neale.

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Note Added

While this manuscript was under final review, a paper on the efficacy of 2-PMPA in PPI appeared in Brain Research 1371:82, 2011.

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Profaci, C.P., Krolikowski, K.A., Olszewski, R.T. et al. Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP and d-amphetamine models of schizophrenia. Psychopharmacology 216, 235–243 (2011). https://doi.org/10.1007/s00213-011-2200-0

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