title: Environmental enrichment alters protein expression as well as the proteomic response to cocaine in rat nucleus accumbens.
abstract: Prior research demonstrated that environmental enrichment creates individual differences in behavior leading to a protective addiction phenotype in rats. Understanding the mechanisms underlying this phenotype will guide selection of targets for much-needed novel pharmacotherapeutics. The current study investigates differences in proteome expression in the nucleus accumbens of enriched and isolated rats and the proteomic response to cocaine self-administration using a liquid chromatography mass spectrometry (LCMS) technique to quantify 1917 proteins. Results of complementary Ingenuity Pathways Analyses (IPA) and gene set enrichment analyses (GSEA), both performed using protein quantitative data, demonstrate that cocaine increases vesicular transporters for dopamine and glutamate as well as increasing proteins in the RhoA pathway. Further, cocaine regulates proteins related to ERK, CREB and AKT signaling. Environmental enrichment altered expression of a large number of proteins implicated in a diverse number of neuronal functions (e.g., energy production, mRNA splicing, and ubiquitination), molecular cascades (e.g., protein kinases), psychiatric disorders (e.g., mood disorders), and neurodegenerative diseases (e.g., Huntington's and Alzheimer's diseases). Upregulation of energy metabolism components in EC rats was verified using RNA sequencing. Most of the biological functions and pathways listed above were also identified in the Cocaine X Enrichment interaction analysis, providing clear evidence that enriched and isolated rats respond quite differently to cocaine exposure. The overall impression of the current results is that enriched saline-administering rats have a unique proteomic complement compared to enriched cocaine-administering rats as well as saline and cocaine-taking isolated rats. These results identify possible mechanisms of the protective phenotype and provide fertile soil for developing novel pharmacotherapeutics. Proteomics data are available via ProteomeXchange with identifier PXD000990.
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Cheryl F
authors.initials: CF
authors.lastname: Lichti
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch Galveston, TX, USA ; Center for Addiction Research, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: English
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch Galveston, TX, USA ; Center for Addiction Research, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch Galveston, TX, USA ; Center for Addiction Research, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Dingge
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Fanping
authors.initials: F
authors.lastname: Kong
authors.affiliation: Sealy Center for Molecular Medicine, Institute for Translational Science, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Mala
authors.initials: M
authors.lastname: Sinha
authors.affiliation: Sealy Center for Molecular Medicine, Institute for Translational Science, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Clark R
authors.initials: CR
authors.lastname: Andersen
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch Galveston, TX, USA ; Sealy Center for Molecular Medicine, Institute for Translational Science, The University of Texas Medical Branch Galveston, TX, USA ; Department of Preventative Medicine and Community Health, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Spratt
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch Galveston, TX, USA ; Sealy Center for Molecular Medicine, Institute for Translational Science, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Luxon
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch Galveston, TX, USA ; Center for Addiction Research, The University of Texas Medical Branch Galveston, TX, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Green
keywords: cocaine; differential rearing; drug abuse; drug addiction; label-free quantification; proteomics
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