title: Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain.
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.
authors: RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
authors: Juan M
authors: JM
authors: Lima-Ojeda
authors: Miriam A
authors: MA
authors: Vogt
authors: Natascha
authors: N
authors: Pfeiffer
authors: Christof
authors: C
authors: Dormann
authors: Georg
authors: G
authors: Köhr
authors: Rolf
authors: R
authors: Sprengel
authors: Peter
authors: P
authors: Gass
authors: Dragos
authors: D
authors: Inta
mesh_terms: D000367:Age Factors; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006213:Hallucinogens / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced*; D010636:Phenols / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D000928:Antidepressive Agents; D018840:HSP70 Heat-Shock Proteins; D006213:Hallucinogens; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D016291:Dizocilpine Maleate; D053148:Caspase 3
keywords: Antidepressant; DG; GluN2B; Hsp70; MK-801; NMDAR; Neurotoxicity; P7; Postnatal Day 7; Retrosplenial cortex; dentate gyrus; heat shock protein 70; i.p; intraperitoneal; n-methyl-d-aspartate receptors