title: Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity.
abstract: D-aspartate levels in the brain are regulated by the catabolic enzyme D-aspartate oxidase (DDO). D-aspartate activates NMDA receptors, and influences brain connectivity and behaviors relevant to schizophrenia in animal models. In addition, recent evidence reported a significant reduction of D-aspartate levels in the post-mortem brain of schizophrenia-affected patients, associated to higher DDO activity. In the present work, microdialysis experiments in freely moving mice revealed that exogenously administered D-aspartate efficiently cross the blood brain barrier and stimulates L-glutamate efflux in the prefrontal cortex (PFC). Consistently, D-aspartate was able to evoke L-glutamate release in a preparation of cortical synaptosomes through presynaptic stimulation of NMDA, mGlu5 and AMPA/kainate receptors. In support of a potential therapeutic relevance of D-aspartate metabolism in schizophrenia, in vitro enzymatic assays revealed that the second-generation antipsychotic olanzapine, differently to clozapine, chlorpromazine, haloperidol, bupropion, fluoxetine and amitriptyline, inhibits the human DDO activity. In line with in vitro evidence, chronic systemic administration of olanzapine induces a significant extracellular release of D-aspartate and L-glutamate in the PFC of freely moving mice, which is suppressed in Ddo knockout animals. These results suggest that the second-generation antipsychotic olanzapine, through the inhibition of DDO activity, increases L-glutamate release in the PFC of treated mice.
authors.affiliation: Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell'Insubria, 21100, Varese, Italy.|The Protein Factory, Politecnico di Milano and Università degli studi dell'Insubria, 20131, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sacchi
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, The Second University of Naples (SUN), 80138, Naples, Italy.
authors.forename: Vito De
authors.initials: V
authors.lastname: Novellis
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, 44100, Ferrara, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Paolone
authors.affiliation: Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, 80145, Naples, Italy.|Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples (SUN), 81100, Caserta, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Nuzzo
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, The Second University of Naples (SUN), 80138, Naples, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Iannotta
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, The Second University of Naples (SUN), 80138, Naples, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Belardo
authors.affiliation: Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, 80145, Naples, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Squillace
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, 44100, Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bolognesi
authors.affiliation: Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell'Insubria, 21100, Varese, Italy.|The Protein Factory, Politecnico di Milano and Università degli studi dell'Insubria, 20131, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Rosini
authors.affiliation: Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell'Insubria, 21100, Varese, Italy.
authors.forename: Zoraide
authors.initials: Z
authors.lastname: Motta
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, 44100, Ferrara, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Frassineti
authors.affiliation: Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, 70121, Bari, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
authors.affiliation: Dipartimento di Biotecnologie e Scienze della Vita, Università degli studi dell'Insubria, 21100, Varese, Italy.|The Protein Factory, Politecnico di Milano and Università degli studi dell'Insubria, 20131, Milano, Italy.
authors.forename: Loredano
authors.initials: L
authors.lastname: Pollegioni
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, 44100, Ferrara, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, The Second University of Naples (SUN), 80138, Naples, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.affiliation: Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, 80145, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", 80131, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Errico
authors.affiliation: Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, 80145, Naples, Italy.|Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples (SUN), 81100, Caserta, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D050804:D-Aspartate Oxidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000378:metabolism; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001569:Benzodiazepines; D003024:Clozapine; D050804:D-Aspartate Oxidase; D018698:Glutamic Acid; D016202:N-Methylaspartate; D000077152:Olanzapine; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors