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Psychopharmacology (Berl). 2016 Apr;233(8):1349-59. doi: 10.1007/s00213-016-4230-0. Epub 2016 Feb 10.

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia.

Engel M1,2,3,4, Snikeris P5,6,7, Matosin N5,6,7, Newell KA5,6,7, Huang XF5,6,7, Frank E5,7.

Author information

1
Schizophrenia Research Institute, Sydney, Australia. mengel@uow.edu.au.
2
Faculty of Science Medicine and Health, University of Wollongong, Wollongong, Australia. mengel@uow.edu.au.
3
Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia. mengel@uow.edu.au.
4
School of Biological Sciences, University of Wollongong, Wollongong, Australia. mengel@uow.edu.au.
5
Schizophrenia Research Institute, Sydney, Australia.
6
Faculty of Science Medicine and Health, University of Wollongong, Wollongong, Australia.
7
Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia.

Abstract

RATIONALE:

An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored.

OBJECTIVES:

We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia.

METHODS:

Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions.

RESULTS:

In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine.

CONCLUSIONS:

We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3.

KEYWORDS:

Antipsychotic; Phencyclidine; Two hit; mGluR2/3, LY379268, agonist, NMDA receptor, GABAA receptor, schizophrenia, neuregulin 1

PMID:
26861891
DOI:
10.1007/s00213-016-4230-0
[Indexed for MEDLINE]

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