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The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat

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Abstract

Rationale

Current antipsychotics are ineffective at treating the negative and cognitive symptoms of schizophrenia, so there is a substantial need to develop more effective therapeutics for this debilitating disorder. The type II metabotropic glutamate receptor (mGluR2/3) is a novel, potential therapeutic target requiring evaluation in appropriate preclinical models of schizophrenia.

Objective

This study evaluated the potent, selective mGluR2/3 agonist, LY379268, on the behavioural deficits induced by rearing rat pups in social isolation from weaning, a neurodevelopmental model of schizophrenia, to investigate its antipsychotic potential.

Methods

Male Lister Hooded rats were weaned on post-natal day 23–25 and either group-housed (3–4 per cage) or isolation-reared for 6 weeks. At subsequent weekly intervals, animals received acute systemic injection of either vehicle or LY379268 (1 mg/kg; i.p.) 30 min prior to recording locomotor activity in a novel arena, novel object recognition, pre-pulse inhibition of acoustic startle and conditioned emotional response paradigms.

Results

Isolation rearing induced locomotor hyperactivity, deficits in novel object recognition, conditioned emotional behaviour and attenuated the magnitude of the initial acoustic startle response in the PPI paradigm compared to that of group-housed controls. LY379268 reversed the isolation-induced locomotor hyperactivity, the object recognition deficit, and restored startle responses in isolated animals, whilst having no effect on conditioned emotional response impairments.

Conclusions

These data show that LY379268 can reverse some, but not all, post-weaning social isolation-induced changes which have translational relevance to core symptom defects in schizophrenia and support a potential therapeutic role of mGluR2/3 agonists in its treatment.

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Abbreviations

LY379268:

((−)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid)

mGluR2/3:

(Metabotropic glutamate receptor type 2/3)

PND:

(Post-natal day)

LMA:

(Locomotor activity)

NOR:

(Novel object recognition)

PPI:

(Pre-pulse inhibition of acoustic startle)

CER:

(Conditioned emotional response)

ITI:

(Inter-trial interval)

ANOVA:

(Analysis of variance)

PFC:

(Prefrontal cortex)

NAcc:

(Nucleus accumbens)

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Acknowledgements

The authors would like to thank Dr. Janice W Smith and Eli Lilly for the generous donation of LY379268 and Miss Stacey Knapp and Mr. Ian Topham for their technical assistance. This work was supported by the BBSRC and University of Nottingham.

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Authors and Affiliations

  1. School of Biomedical Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK

    Caitlin A. Jones, Angus M. Brown & Kevin. C. F. Fone

  2. Division of Academic Radiology, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK

    Dorothee P. Auer

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  1. Caitlin A. Jones
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  2. Angus M. Brown
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  3. Dorothee P. Auer
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  4. Kevin. C. F. Fone
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Correspondence to Kevin. C. F. Fone.

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Jones, C.A., Brown, A.M., Auer, D.P. et al. The mGluR2/3 agonist LY379268 reverses post-weaning social isolation-induced recognition memory deficits in the rat. Psychopharmacology 214, 269–283 (2011). https://doi.org/10.1007/s00213-010-1931-7

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