title: Cocaine hijacks σ1 receptor to initiate induction of activated leukocyte cell adhesion molecule: implication for increased monocyte adhesion and migration in the CNS.
abstract: Human immunodeficiency virus (HIV)-associated increase in monocyte adhesion and trafficking is exacerbated by cocaine abuse. The underlying mechanisms involve cocaine-mediated upregulation of adhesion molecules with subsequent disruption of the blood-brain barrier (BBB). Recently, a novel activated leukocyte cell adhesion molecule (ALCAM) has been implicated in leukocyte transmigration across the endothelium. We now show that upregulation of ALCAM in the brain endothelium seen in HIV(+)/cocaine drug abusers paralleled increased CD68 immunostaining compared with HIV(+)/no cocaine or uninfected controls, suggesting the important role of ALCAM in promoting leukocyte infiltration across the BBB. Furthermore, ALCAM expression was increased in cocaine-treated mice with concomitant increase in monocyte adhesion and transmigration in vivo, which was ameliorated by pretreating with the neutralizing antibody to ALCAM, lending additional support to the role of ALCAM. This new concept was further confirmed by in vitro experiments. Cocaine-mediated induction of ALCAM in human brain microvascular endothelial cells through the translocation of σ receptor to the plasma membrane, followed by phosphorylation of PDGF-β (platelet-derived growth factor-β) receptor. Downstream activation of mitogen-activated protein kinases, Akt, and NF-κB (nuclear factor-κB) pathways resulted in induced expression of ALCAM. Functional implication of upregulated ALCAM was confirmed using cell adhesion and transmigration assays. Neutralizing antibody to ALCAM ameliorated this effect. Together, these findings implicate cocaine-mediated induction of ALCAM as a mediator of increased monocyte adhesion/transmigration into the CNS.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
authors.forename: Keejun
authors.initials: K
authors.lastname: Kim
authors.forename: Ming
authors.initials: M
authors.lastname: Duan
authors.forename: Teruo
authors.initials: T
authors.lastname: Hayashi
authors.forename: Minglei
authors.initials: M
authors.lastname: Guo
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.forename: Alexander
authors.initials: A
authors.lastname: Prat
authors.forename: John
authors.initials: J
authors.lastname: Wang
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
mesh_terms: D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003042:Cocaine / Q000276:immunology / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D017480:Receptors, sigma / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020410:Activated-Leukocyte Cell Adhesion Molecule; D016328:NF-kappa B; D017480:Receptors, sigma; D003042:Cocaine