Multidimensional Top-Down Proteomics of Brain-Region-Specific Mouse Brain Proteoforms Responsive to Cocaine and Estradiol

Hae Min Park, Rosalba Satta, Roderick G. Davis, Young Ah Goo, Richard D. Leduc, Ryan T. Fellers, Joseph B. Greer, Elena V. Romanova, Stanislav S. Rubakhin, Rex Tai, Paul M. Thomas, Jonathan V. Sweedler, Neil L. Kelleher, Steven M. Patrie, Amy W. Lasek

Research output: Contribution to journalArticle

Abstract

Cocaine addiction afflicts nearly 1 million adults in the United States, and to date, there are no known treatments approved for this psychiatric condition. Women are particularly vulnerable to developing a cocaine use disorder and suffer from more serious cardiac consequences than men when using cocaine. Estrogen is one biological factor contributing to the increased risk for females to develop problematic cocaine use. Animal studies have demonstrated that estrogen (17β-estradiol or E2) enhances the rewarding properties of cocaine. Although E2 affects the dopamine system, the molecular and cellular mechanisms of E2-enhanced cocaine reward have not been characterized. In this study, quantitative top-down proteomics was used to measure intact proteins in specific regions of the female mouse brain after mice were trained for cocaine-conditioned place preference, a behavioral test of cocaine reward. Several proteoform changes occurred in the ventral tegmental area after combined cocaine and E2 treatments, with the most numerous proteoform alterations on myelin basic protein, indicating possible changes in white matter structure. There were also changes in histone H4, protein phosphatase inhibitors, cholecystokinin, and calmodulin proteoforms. These observations provide insight into estrogen signaling in the brain and may guide new approaches to treating women with cocaine use disorder.

Original languageEnglish (US)
Pages (from-to)3999-4012
Number of pages14
JournalJournal of Proteome Research
Volume18
Issue number11
DOIs
StatePublished - Nov 1 2019

Keywords

  • addiction
  • cocaine
  • estrogen
  • label-free quantification
  • proteoforms
  • top-down mass spectrometry

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

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    Park, H. M., Satta, R., Davis, R. G., Goo, Y. A., Leduc, R. D., Fellers, R. T., Greer, J. B., Romanova, E. V., Rubakhin, S. S., Tai, R., Thomas, P. M., Sweedler, J. V., Kelleher, N. L., Patrie, S. M., & Lasek, A. W. (2019). Multidimensional Top-Down Proteomics of Brain-Region-Specific Mouse Brain Proteoforms Responsive to Cocaine and Estradiol. Journal of Proteome Research, 18(11), 3999-4012. https://doi.org/10.1021/acs.jproteome.9b00481