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          Institute: MPI für medizinische Forschung     Collection: Jahbruch 2014_archival     Display Documents



ID: 681458.0, MPI für medizinische Forschung / Jahbruch 2014_archival
Pharmacological blockade of GluN2B−containing NMDA receptors induces antidepressant−like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain
Translation of Title:Pharmacological blockade of GluN2B−containing NMDA receptors induces antidepressant−like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain
Authors:Lima−Ojeda, Juan M.; Vogt, Miriam A.; Pfeiffer, Natascha; Dorman, Christof; Köhr, Georg; Sprengel, Rolf; Gass, Peter; Inta, Dragos
Language:English
Date of Publication (YYYY-MM-DD):2013-08-01
Title of Journal:Progress in Neuro−Psychopharmacology& Biological Psychiatry
Journal Abbrev.:Progress in Neuro−Psychopharmacology& Biological P
Volume:45
Start Page:28
End Page:33
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description: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
Free Keywords:Antidepressant;
GluN2B;
MK−801;
Neurotoxicity;
Retrosplenial cortex
External Publication Status:published
Document Type:Article
Communicated by:wkaiser
Affiliations:MPI für medizinische Forschung/Abteilung Molekulare Neurobiologie
MPI für medizinische Forschung/Abteilung Zellphysiologie/Olfaction Web
MPI für medizinische Forschung/Abteilung Molekulare Neurobiologie/Gruppe Georg Köhr
MPI für medizinische Forschung/Abteilung Molekulare Neurobiologie/Gruppe Rolf Sprengel
Identifiers:LOCALID:7912
URI:http%3A%2F%2Fwww.sciencedirect.com%2Fscience%3F_ob...
URI:http%3A%2F%2Fdx.doi.org%2F10.1016%2Fj.pnpbp.2013.0...
URI:http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpubmed%2F23643...
DOI:10.1016%2Fj.pnpbp.2013.04.017
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