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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.

SUBMITTER: Sacchi S

PROVIDER: S-EPMC5385520 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity.

Sacchi Silvia S Novellis Vito De V Paolone Giovanna G Nuzzo Tommaso T Iannotta Monica M Belardo Carmela C Squillace Marta M Bolognesi Paolo P Rosini Elena E Motta Zoraide Z Frassineti Martina M Bertolino Alessandro A Pollegioni Loredano L Morari Michele M Maione Sabatino S Errico Francesco F Usiello Alessandro A

Scientific reports 20170410

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 exogenousl ...[more]

PMID: 28393897

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Project description:BackgroundSecond generation antipsychotics (SGAs) induce glucometabolic side-effects, such as hyperglycemia and insulin resistance, which pose a therapeutic challenge for mental illness. Sphingolipids play a role in glycaemic balance and insulin resistance. Endoplasmic reticulum (ER) stress contributes to impaired insulin signalling and whole-body glucose intolerance. Diabetogenic SGA effects on ER stress and sphingolipids, such as ceramide and sphingomyelin, in peripheral metabolic tissues are unknown. This study aimed to investigate the acute effects of clozapine and olanzapine on ceramide and sphingomyelin levels, and protein expression of key enzymes involved in lipid and glucose metabolism, in the liver and skeletal muscle.MethodsFemale rats were administered olanzapine (1 mg/kg), clozapine (12 mg/kg), or vehicle (control) and euthanized 1-h later. Ceramide and sphingomyelin levels were examined using electrospray ionization (ESI) mass spectrometry. Expression of lipid enzymes (ceramide synthase 2 (CerS2), elongation of very long-chain fatty acid 1 (ELOVL1), fatty acid synthase (FAS) and acetyl CoA carboxylase 1 (ACC1)), ER stress markers (inositol-requiring enzyme 1 (IRE1) and eukaryotic initiation factor (eIF2α) were also examined.ResultsClozapine caused robust reductions in hepatic ceramide and sphingolipid levels (p < 0.0001), upregulated CerS2 (p < 0.05) and ELOVL1 (+ 37%) and induced significant hyperglycemia (vs controls). In contrast, olanzapine increased hepatic sphingomyelin levels (p < 0.05 vs controls). SGAs did not alter sphingolipid levels in the muscle. Clozapine increased (+ 52.5%) hepatic eIF2α phosphorylation, demonstrating evidence of activation of the PERK/eIF2α ER stress axis. Hepatic IRE1, FAS and ACC1 were unaltered.ConclusionsThis study provides the first evidence that diabetogenic SGAs disrupt hepatic sphingolipid homeostasis within 1-h of administration. Sphingolipids may be key candidates in the mechanisms underlying the diabetes side-effects of SGAs; however, further research is required.

Dataset Information

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity.

Publications

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity.

Similar Datasets

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