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NMDA receptor antagonism: from modeling schizophrenia to treating refractory depression

Jiménez-Sánchez, Laura and Campa, Leticia and Auberson, Yves and Adell, Albert (2014) NMDA receptor antagonism: from modeling schizophrenia to treating refractory depression. Neuropsychopharmacology.

Abstract

Due to the adverse side effects of ketamine, much research is focused in improving the pharmacological profile of NMDA receptor antagonists by investigating whether subtype-selective could achieve a better antidepressant efficacy. In this regard, preclinical studies have shown that the GluN2B receptor antagonist, Ro 25-6981, possesses antidepressant-like effects. Furthermore, several investigational drugs have manifested some efficacy in the treatment of depressive states, such as the GluN2B receptor antagonists CP-101,606 and MK 0657, the NMDA receptor glycine-site partial agonist GLYX-13, and the low-trapping nonselective NMDA channel blocker AZD6765. To study the role of the selective blockade of GluN2A and GluN2B subunits in the acute NMDA receptor antagonist model of schizophrenia as well as in the treatment of depression, we have examined the biochemical and behavioral changes elicited by antagonists selective for the GluN2A (NVP-AAM077)and GluN2B (Ro 25-6981) subunits. The results are compared with the effects of a nonselective NMDA receptor channel blocker such as dizocilpine (MK-801). The antidepressant-like effects were measured in the forced swim test (FST) while the possible emergence of psychotomimetic adverse effects was associated with the ability to induce stereotypical behavior. In summary, the blockade of both subunits is necessary to develop psychotic-like effects whereas the blockade of one of these subunits is sufficient to elicit an antidepressant-like action in the FST. Further research is needed to warrant the potential antidepressant role of selective GluN2A receptor antagonists and the risk factors of abuse liability and cognitive impairment after sustained exposure.

Item Type: Article
Keywords: NVP-AAM077; NMDA; GluN2A
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/21322

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