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Interaction of mGlu2/3 agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats

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Abstract

Rationale

Subchronic administration to rodents of the N-methyl-d-aspartate non-competitive antagonist, phencyclidine (PCP), impairs novel object recognition (NOR). Atypical antipsychotic drugs (APDs) reverse the effects of subchronic PCP on NOR. The effect of metabotropic glutamate2/3 receptor (mGlu2/3) agonists upon NOR is unknown.

Objectives and methods

We tested the hypotheses that the mGlu2/3 agonist, LY379268, by itself, or in combination with APDs or pimavanserin, a 5-HT2A inverse agonist, would reverse the deficit in NOR induced by subchronic treatment with PCP (2 mg/kg, b.i.d., for 7 days).

Results

The mGlu2/3 agonist LY379268 (1 or 3 mg/kg) did not attenuate the PCP-induced NOR deficit. However, together with sub-effective dose of the atypical APDs, clozapine (0.1 mg/kg) or lurasidone (0.03 mg/kg), but not the typical APD, haloperidol (0.1 mg/kg), or pimavanserin (3 mg/kg), LY379268, 1 mg/kg, significantly reversed the PCP-induced NOR deficit. Moreover, the effect of clozapine was blocked by the mGlu2/3 antagonist, LY341495 (1 mg/kg).

Conclusions

These results indicate that mGlu2/3 agonism can potentiate the ability of atypical, but not typical APDs, to ameliorate the effect of subchronic PCP on NOR, that mGlu2/3 agonism may contribute to the ability of atypical APDs to acutely reverse the effect of subchronic PCP on NOR, but that by itself, mGlu2/3 agonism, is ineffective in this model of cognitive impairment in schizophrenia. These results suggest that mGlu2/3 receptor agonism should be investigated as an adjunctive treatment of cognitive impairment in schizophrenia rather than as monotherapy, which may be effective for control of psychosis, but not for cognitive impairment.

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Acknowledgements

This research was supported, in part, by a grant from Dainippon Sumitomo Pharma Co., Ltd. HYM is supported, in part, by contributions from the Ritter and Weisman Family Foundations.

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Authors and Affiliations

  1. Division of Psychopharmacology, Vanderbilt University Medical Center, Nashville, TN, 37212, USA

    Masakuni Horiguchi, Mei Huang & Herbert Y. Meltzer

  2. Dainippon Sumitomo Pharma Co., Ltd, Osaka, 564–0053, Japan

    Masakuni Horiguchi

  3. Vanderbilt Psychiatric Hospital, 1601 23rd Ave South, Suite 306, Nashville, TN, 37212, USA

    Herbert Y. Meltzer

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  1. Masakuni Horiguchi
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Correspondence to Herbert Y. Meltzer.

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Horiguchi, M., Huang, M. & Meltzer, H.Y. Interaction of mGlu2/3 agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats. Psychopharmacology 217, 13–24 (2011). https://doi.org/10.1007/s00213-011-2251-2

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