Comprehensive Glycomic and Proteomic Analysis of Mouse Striatum and Lateral Hypothalamus Following Repeated Exposures to Cocaine or Methamphetamine

• Published in: Molecular & cellular proteomics Vol. 23; no. 8; p. 100803
• Main Authors: Sethi, Manveen K., Maccioni, Riccardo, Hogan, John D., Kawamura, Tomoya, Repunte-Canonigo, Vez, Chen, Jihuan, Zaia, Joseph, Sanna, Pietro Paolo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2024; American Society for Biochemistry and Molecular Biology
• Subjects: addiction; Animals; chondroitin sulfate; cocaine; Cocaine - pharmacology; Collection: Glycoscience; Corpus Striatum - drug effects; Corpus Striatum - metabolism; drug abuse; Glycomics; glycosaminoglycans; heparan sulfate; Heparitin Sulfate - metabolism; Hypothalamus - drug effects; Hypothalamus - metabolism; lateral hypothalamus; Male; mass spectrometry; methamphetamine; Methamphetamine - pharmacology; Mice; Mice, Inbred C57BL; neurobiology; proteoglycans; Proteome - metabolism; Proteomics; striatum; EPM; cocaine; NCAN; lateral hypothalamus; MYPR; HS; PNN; TENR; drug abuse; striatum; methamphetamine; FDR; neurobiology; mass spectrometry; KEGG; PGs; ARSB; EIC; glycosaminoglycans; proteoglycans; HSPG; proteomics; chondroitin sulfate; MS; addiction; GO; METH; ACN; CHABC; GAG; SYN2; PCA; TIC; CS; SEC; heparan sulfate; glycomics; CALX; AAV; CSPG; HDGF; IPA; LH
• ISSN: 1535-9476; 1535-9484; 1535-9484
• DOI: 10.1016/j.mcpro.2024.100803

Substance use disorder is a major concern, with few therapeutic options. Heparan sulfate (HS) and chondroitin sulfate (CS) interact with a plethora of growth factors and their receptors and have profound effects on cellular signaling. Thus, targeting these dynamic interactions might represent a potential novel therapeutic modality. In the present study, we performed mass spectrometry–based glycomic and proteomic analysis to understand the effects of cocaine and methamphetamine (METH) on HS, CS, and the proteome of two brain regions critically involved in drug addiction: the lateral hypothalamus and the striatum. We observed that cocaine and METH significantly alter HS and CS abundances as well as sulfate contents and composition. In particular, repeated METH or cocaine treatments reduced CS 4-O-sulfation and increased CS 6-O-sulfation. Since C4S and C6S exercise differential effects on axon growth, regeneration, and plasticity, these changes likely contribute to drug-induced neural plasticity in these brain regions. Notably, we observed that restoring these alterations by increasing CS 4-0 levels in the lateral hypothalamus by adeno-associated virus delivery of an shRNA to arylsulfatase B (N-acetylgalactosamine-4-sulfatase) ameliorated anxiety and prevented the expression of preference for cocaine in a novelty induced conditioned place preference test during cocaine withdrawal. Finally, proteomics analyses revealed a number of aberrant proteins in METH- and cocaine-treated versus saline-treated mice, including myelin proteolipid protein, calcium/calmodulin-dependent protein kinase type II subunit alpha, synapsin-2, tenascin-R, calnexin, annexin A7, hepatoma-derived growth factor, neurocan, and CSPG5, and oxidative phosphorylation among the top perturbed pathway. Taken together, these data support the role of HS, CS, and associated proteins in stimulants abuse and suggest that manipulation of HSPGs can represent a novel therapeutic strategy. [Display omitted] •Cocaine and METH significantly alter HS and CS abundances and sulfate contents.•METH/cocaine treatment reduced CS 4-O- and increased CS 6-O-sulfation versus control.•Increasing CS 4-0 by silencing ARSB improved anxiety and prevented cocaine preference.•Proteomics data showed a tight clustering of the drug-treated versus control samples. Drug abuse is a major concern with few therapeutic options. Heparan sulfate and chondroitin sulfate interact with growth factors and their receptors and have profound effects on cellular signaling. Thus, targeting these interactions represents a novel therapeutic modality. We performed glycomic and proteomic analysis of cocaine and methamphetamine-treated mouse brains versus control (saline-treated) from lateral hypothalamus and striatum and identified key alterations in chondroitin sulfate and heparan sulfate sulfation patterns and associated proteins and pathways, opening avenues for novel therapeutic strategies for stimulant abuse.