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Neurochemical Metabolomics Reveals Disruption to Sphingolipid Metabolism Following Chronic Haloperidol Administration

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Abstract

Haloperidol is an effective antipsychotic drug for treatment of schizophrenia, but prolonged use can lead to debilitating side effects. To better understand the effects of long-term administration, we measured global metabolic changes in mouse brain following 3 mg/kg/day haloperidol for 28 days. These conditions lead to movement-related side effects in mice akin to those observed in patients after prolonged use. Brain tissue was collected following microwave tissue fixation to arrest metabolism and extracted metabolites were assessed using both liquid and gas chromatography mass spectrometry (MS). Over 300 unique compounds were identified across MS platforms. Haloperidol was found to be present in all test samples and not in controls, indicating experimental validity. Twenty-one compounds differed significantly between test and control groups at the p < 0.05 level. Top compounds were robust to analytical method, also being identified via partial least squares discriminant analysis. Four compounds (sphinganine, N-acetylornithine, leucine and adenosine diphosphate) survived correction for multiple testing in a non-parametric analysis using false discovery rate threshold < 0.1. Pathway analysis of nominally significant compounds (p < 0.05) revealed significant findings for sphingolipid metabolism (p = 0.015) and protein biosynthesis (p = 0.024). Altered sphingolipid metabolism is suggestive of disruptions to myelin. This interpretation is supported by our observation of elevated N-acetyl-aspartyl-glutamate in the haloperidol-treated mice (p = 0.004), a marker previously associated with demyelination. This study further demonstrates the utility of murine neurochemical metabolomics as a method to advance understanding of CNS drug effects.

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Acknowledgments

We gratefully acknowledge the assistance of Danny Alexander, Edward Karoly and John Luster at Metabolon, Inc, Research Triangle Park, North Carolina. We also acknowledge the assistance of Lindsey King and Krista Scoggins at Virginia Commonwealth University in expediting the experiments. This work was supported by grants from the US National Institutes of Health to EJvdO (R21DA021411) and a NARSAD (National Alliance for Research on Schizophrenia and Depression, now the Brain Research Foundation) Young Investigator Award to JLM. Both JLM and EJvdO are also partly supported by grant 1R01MH097283 from the US National Institute of Mental Health.

Conflict of Interest

After working on this project, REV left Virginia Commonwealth University and is now an employee of Eli Lilly. All other authors declare no potential conflicts of interest.

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Authors and Affiliations

  1. Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, McGuire Hall, 1112 East Clay Street, Richmond, VA, 23298, USA

    Joseph L. McClay, Patrick M. Beardsley & Edwin J. van den Oord

  2. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA

    Sarah A. Vunck, Angela M. Batman, Robert E. Vann & Patrick M. Beardsley

  3. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    James J. Crowley

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  1. Joseph L. McClay
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  2. Sarah A. Vunck
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  7. Edwin J. van den Oord
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Correspondence to Joseph L. McClay.

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McClay, J.L., Vunck, S.A., Batman, A.M. et al. Neurochemical Metabolomics Reveals Disruption to Sphingolipid Metabolism Following Chronic Haloperidol Administration. J Neuroimmune Pharmacol 10, 425–434 (2015). https://doi.org/10.1007/s11481-015-9605-1

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