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  Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain

Lima-Ojeda, J. M., Vogt, M. A., Pfeiffer, N., Dormann, C., Köhr, G., Sprengel, R., et al. (2013). Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain. Progress in Neuro-Psychopharmacology& Biological Psychiatry, 45, 28-33. doi: 10.1016/j.pnpbp.2013.04.017.

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 Creators:
Lima-Ojeda, Juan M., Author
Vogt, Miriam A., Author
Pfeiffer, Natascha, Author
Dormann, Christof, Author
Köhr, Georg1, Author              
Sprengel, Rolf1, Author              
Gass, Peter, Author
Inta, Dragos, Author
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              

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Free keywords: Antidepressant; GluN2B; MK-801; Neurotoxicity; Retrosplenial cortex
 Abstract: NMDA receptor (NMDAR) antagonists like ketamine and MK-801 possess remarkable antidepressant effects with fast onset. However, they over-stimulate the retrosplenial cortex, evoking psychosis-like effects and neuronal injury, revealed by de novo induction of the heat shock protein 70 (Hsp70). Moreover, early in the development MK-801 triggers widespread cortical apoptosis, inducing extensive caspase-3 expression. Altogether these data raise strong concerns on the clinical applicability of NMDAR antagonist therapies. Therefore, the development of novel therapeutics targeting more specifically NMDAR to avoid psychotomimetic effects is necessary. Here we investigated a GluN2B (NR2B) antagonist in behavioral and neurotoxicity paradigms in rats to assess its potential as possible alternative to unspecific NMDA receptor antagonists. We found that treatment with the GluN2B specific antagonist Ro 25-6981 evoked robust antidepressant-like effects. Moreover, Ro 25-6981 did not cause hyperactivity as displayed after treatment with unspecific NMDAR antagonists, a correlate of psychosis-like effects in rodents. Additionally, Ro 25-6981, unlike MK-801, did not induce caspase-3 and HSP70 expression, markers of neurotoxicity in the perinatal and adult brain, respectively. Moreover, unexpectedly, in the adult retrosplenial cortex Ro 25-6981 pretreatment significantly reduced MK-801-triggered neurotoxicity. Our results suggest that GluN2B antagonists may represent valuable alternatives to unspecific NMDAR antagonists with robust antidepressant efficacy and a more favorable side-effect profile.

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Language(s): eng - English
 Dates: 2013-04-222012-12-222013-04-232013-04-302013-08-01
 Publication Status: Published in print
 Pages: 6
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.pnpbp.2013.04.017
Other: 7912
 Degree: -

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Title: Progress in Neuro-Psychopharmacology& Biological Psychiatry
Source Genre: Journal
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Pages: - Volume / Issue: 45 Sequence Number: - Start / End Page: 28 - 33 Identifier: -