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Combined administration of an mGlu2/3 receptor agonist and a 5-HT2A receptor antagonist markedly attenuate the psychomotor-activating and neurochemical effects of psychostimulants

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Abstract

Rationale

It was recently reported that administration of the metabotropic glutamate 2 and 3 (mGlu2/3) receptor agonist prodrug LY2140023 to schizophrenic patients decreased positive symptoms. However, at the single, potentially suboptimal, dose that was tested, LY2140023 trended towards being inferior to olanzapine on several indices of efficacy within the Positive and Negative Syndrome Scale.

Objectives

In this study, we examined whether the antipsychotic potential of mGlu2/3 receptor agonism can be enhanced with 5-HT2A receptor antagonism.

Materials and methods

Specifically, we characterized the effects of coadministering submaximally effective doses of the 5-HT2A receptor antagonist M100907 (0.2 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg) on amphetamine-induced and MK-801-induced psychomotor activity in rats, an assay sensitive to antipsychotics. We also determined the effects of coadministering these two compounds on MK-801-induced dopamine and norepinephrine efflux in the nucleus accumbens (NAc).

Results

At the submaximally effective doses tested, the effects of M100907 and LY379268 on amphetamine-induced and MK-801-induced psychomotor activity were significantly greater when given together than when given separately. Furthermore, coadministration of these doses of M100907 and LY379268 reduced MK-801-induced dopamine efflux in the NAc. This effect on dopamine release was not observed with the administration of either compound alone, even at higher doses that attenuated MK-801-induced psychomotor activity.

Conclusions

Our results suggest that a single compound having both mGlu2/3 receptor agonist and 5-HT2A receptor antagonist activity, or coadministration of two compounds selective for these receptors, could be superior in terms of efficacy and/or reduced side-effect liability relative to an mGlu2/3 receptor agonist alone.

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Acknowledgements

The authors would like to thank Marlene Jacobson for the helpful comments and discussion regarding the manuscript. In addition, the authors thank Merck’s drug metabolism and pharmacokinetics group for the analysis of MK-801 concentration in the brain and the medicinal chemistry group for the synthesis of LY379268 and M100907. These studies were supported by Merck & Co., Inc., West Point, PA, USA from where all authors are employed. No direct conflict of interest is anticipated and there are no biomedical financial interests regarding this report.

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Authors and Affiliations

  1. Department of Schizophrenia Research, Merck & Co., Inc., WP46-100, 770 Sumneytown Pike, P.O. Box 4, West Point, PA, 19486, USA

    Jason M. Uslaner, Sean M. Smith, Sarah L. Huszar, Rashida Pachmerhiwala, Richard M. Hinchliffe, Joshua D. Vardigan & Pete H. Hutson

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  1. Jason M. Uslaner
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  2. Sean M. Smith
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Correspondence to Jason M. Uslaner.

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Jason M. Uslaner and Sean M. Smith denote equal contribution to the experiments and the manuscript.

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Uslaner, J.M., Smith, S.M., Huszar, S.L. et al. Combined administration of an mGlu2/3 receptor agonist and a 5-HT2A receptor antagonist markedly attenuate the psychomotor-activating and neurochemical effects of psychostimulants. Psychopharmacology 206, 641–651 (2009). https://doi.org/10.1007/s00213-009-1644-y

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