1. Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity.
- Author
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Sacchi S, Novellis V, Paolone G, Nuzzo T, Iannotta M, Belardo C, Squillace M, Bolognesi P, Rosini E, Motta Z, Frassineti M, Bertolino A, Pollegioni L, Morari M, Maione S, Errico F, and Usiello A
- Subjects
- Animals, Benzodiazepines chemistry, Clozapine pharmacology, D-Aspartate Oxidase genetics, D-Aspartate Oxidase metabolism, Dose-Response Relationship, Drug, Enzyme Activation drug effects, Humans, Male, Mice, Mice, Knockout, N-Methylaspartate metabolism, Olanzapine, Receptors, N-Methyl-D-Aspartate metabolism, Selective Serotonin Reuptake Inhibitors chemistry, Benzodiazepines pharmacology, D-Aspartate Oxidase antagonists & inhibitors, Glutamic Acid metabolism, Prefrontal Cortex drug effects, Prefrontal Cortex metabolism, Selective Serotonin Reuptake Inhibitors pharmacology
- 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.
- Published
- 2017
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