PMID- 25063582 OWN - NLM STAT- MEDLINE DCOM- 20150714 LR - 20161125 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 86 DP - 2014 Nov TI - Levels of the Rab GDP dissociation inhibitor (GDI) are altered in the prenatal restrain stress mouse model of schizophrenia and are differentially regulated by the mGlu2/3 receptor agonists, LY379268 and LY354740. PG - 133-44 LID - S0028-3908(14)00271-8 [pii] LID - 10.1016/j.neuropharm.2014.07.009 [doi] AB - LY379268 and LY354740, two agonists of mGlu2/3 metabotropic glutamate receptors, display different potencies in mouse models of schizophrenia. This differential effect of the two drugs remains unexplained. We performed a proteomic analysis in cultured cortical neurons challenged with either LY379268 or LY354740. Among the few proteins that were differentially influenced by the two drugs, Rab GDP dissociation inhibitor-beta (Rab GDIbeta) was down-regulated by LY379268 and showed a trend to an up-regulation in response to LY354740. In cultured hippocampal neurons, LY379268 selectively down-regulated the alpha isoform of Rab GDI. Rab GDI inhibits the activity of the synaptic vesicle-associated protein, Rab3A, and is reduced in the brain of schizophrenic patients. We examined the expression of Rab GDI in mice exposed to prenatal stress ("PRS mice"), which have been described as a putative model of schizophrenia. Rab GDIalpha protein levels were increased in the hippocampus of PRS mice at postnatal days (PND)1 and 21, but not at PND60. At PND21, PRS mice also showed a reduced depolarization-evoked [(3)H]d-aspartate release in hippocampal synaptosomes. The increase in Rab GDIalpha levels in the hippocampus of PRS mice was reversed by a 7-days treatment with LY379268 (1 or 10 mg/kg, i.p.), but not by treatment with equal doses of LY354740. These data strengthen the validity of PRS mice as a model of schizophrenia, and show for the first time a pharmacodynamic difference between LY379268 and LY354740 which might be taken into account in an attempt to explain the differential effect of the two drugs across mouse models. CI - Copyright (c) 2014 Elsevier Ltd. All rights reserved. FAU - Orlando, Rosamaria AU - Orlando R AD - IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, Enna, Italy. FAU - Borro, Marina AU - Borro M AD - NESMOS Department, Advanced Molecular Diagnostic Unit, Sapienza University, Sant'Andrea Hospital, Rome, Italy. FAU - Motolese, Marta AU - Motolese M AD - IRCCS Neuromed, Pozzilli, Italy. FAU - Molinaro, Gemma AU - Molinaro G AD - IRCCS Neuromed, Pozzilli, Italy. FAU - Scaccianoce, Sergio AU - Scaccianoce S AD - Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy. FAU - Caruso, Alessandra AU - Caruso A AD - Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy. FAU - di Nuzzo, Luigi AU - di Nuzzo L AD - Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy. FAU - Caraci, Filippo AU - Caraci F AD - IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, Enna, Italy; Department of Educational Sciences, University of Catania, Catania, Italy. FAU - Matrisciano, Francesco AU - Matrisciano F AD - IRCCS Centro Neurolesi Bonino Pulejo, Messina, Italy. FAU - Pittaluga, Anna AU - Pittaluga A AD - Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genoa, Genoa, Italy. FAU - Mairesse, Jerome AU - Mairesse J AD - Neural Plasticity Team, Universite Lille 1, International Associated Laboratory (LIA), France. FAU - Simmaco, Maurizio AU - Simmaco M AD - NESMOS Department, Advanced Molecular Diagnostic Unit, Sapienza University, Sant'Andrea Hospital, Rome, Italy. FAU - Nistico, Robert AU - Nistico R AD - Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy. FAU - Monn, James A AU - Monn JA AD - Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, IN 46285, USA. FAU - Nicoletti, Ferdinando AU - Nicoletti F AD - IRCCS Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, University of Rome Sapienza, Rome, Italy. Electronic address: ferdinandonicoletti@hotmail.com. LA - eng PT - Comparative Study PT - Journal Article DEP - 20140722 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Amino Acids) RN - 0 (Antipsychotic Agents) RN - 0 (Bridged Bicyclo Compounds) RN - 0 (Bridged Bicyclo Compounds, Heterocyclic) RN - 0 (GDP dissociation inhibitor 1) RN - 0 (Guanine Nucleotide Dissociation Inhibitors) RN - 0 (LY 379268) RN - 0 (Receptors, Metabotropic Glutamate) RN - 4SR0Q8YD1X (D-Aspartic Acid) RN - ONU5A67T2S (eglumetad) SB - IM MH - Amino Acids/*pharmacology MH - Animals MH - Antipsychotic Agents/*pharmacology MH - Bridged Bicyclo Compounds/*pharmacology MH - Bridged Bicyclo Compounds, Heterocyclic/*pharmacology MH - Cells, Cultured MH - D-Aspartic Acid/metabolism MH - Disease Models, Animal MH - Epigenesis, Genetic MH - Female MH - Guanine Nucleotide Dissociation Inhibitors/*metabolism MH - Hippocampus/drug effects/growth & development/metabolism MH - Male MH - Mice MH - Pregnancy MH - Prenatal Exposure Delayed Effects MH - Proteomics/methods MH - Receptors, Metabotropic Glutamate/agonists/metabolism MH - Restraint, Physical MH - Schizophrenia/*drug therapy/*metabolism OTO - NOTNLM OT - LY354740 OT - LY379268 OT - Prenatal stress OT - Rab GDI OT - Schizophrenia EDAT- 2014/07/27 06:00 MHDA- 2015/07/15 06:00 CRDT- 2014/07/27 06:00 PHST- 2013/10/21 00:00 [received] PHST- 2014/07/07 00:00 [revised] PHST- 2014/07/09 00:00 [accepted] PHST- 2014/07/27 06:00 [entrez] PHST- 2014/07/27 06:00 [pubmed] PHST- 2015/07/15 06:00 [medline] AID - S0028-3908(14)00271-8 [pii] AID - 10.1016/j.neuropharm.2014.07.009 [doi] PST - ppublish SO - Neuropharmacology. 2014 Nov;86:133-44. doi: 10.1016/j.neuropharm.2014.07.009. Epub 2014 Jul 22.