Abstract
Paradoxically, N-methyl-D-aspartate (NMDA) receptor antagonists are used to model certain aspects of schizophrenia as well as to treat refractory depression. However, the role of different subunits of the NMDA receptor in both conditions is poorly understood. Here we used biochemical and behavioral readouts to examine the in vivo prefrontal efflux of serotonin and glutamate as well as the stereotypical behavior and the antidepressant-like activity in the forced swim test elicited by antagonists selective for the GluN2A (NVP-AAM077) and GluN2B (Ro 25-6981) subunits. The effects of the non-subunit selective antagonist, MK-801; were also studied for comparison. The administration of MK-801 dose dependently increased the prefrontal efflux of serotonin and glutamate and markedly increased the stereotypy scores. NVP-AAM077 also increased the efflux of serotonin and glutamate, but without the induction of stereotypies. In contrast, Ro 25-6981 did not change any of the biochemical and behavioral parameters tested. Interestingly, the administration of NVP-AAM077 and Ro 25-6981 alone elicited antidepressant-like activity in the forced swim test, in contrast to the combination of both compounds that evoked marked stereotypies. Our interpretation of the results is that both GluN2A and GluN2B subunits are needed to induce stereotypies, which might be suggestive of potential psychotomimetic effects in humans, but the antagonism of only one of these subunits is sufficient to evoke an antidepressant response. We also propose that GluN2A receptor antagonists could have potential antidepressant activity in the absence of potential psychotomimetic effects.
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Acknowledgements
L Jiménez-Sánchez was the recipient of a predoctoral fellowship from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). We also thank Novartis for the generous gift of NVP-AAM077. This work was supported by the Instituto de Salud Carlos III, Subdirección General del Evaluación y Fomento de la Investigación (FIS Grants PI10-01103 and PI13-00038) that were co-funded by the European Regional Development Fund (‘A way to build Europe’). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and the Generalitat de Catalunya (2009SGR220) is also acknowledged.
The funding agencies had no role in the design and conduct of the study, collection, management, analyses, and interpretation of the data; and preparation, review, or approval of the manuscript and the decision to submit it for publication.
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Jiménez-Sánchez, L., Campa, L., Auberson, Y. et al. The Role of GluN2A and GluN2B Subunits on the Effects of NMDA Receptor Antagonists in Modeling Schizophrenia and Treating Refractory Depression. Neuropsychopharmacol 39, 2673–2680 (2014). https://doi.org/10.1038/npp.2014.123
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DOI: https://doi.org/10.1038/npp.2014.123
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