Cocaine hijacks δ1 receptor to initiate induction of activated leukocyte cell adhesion molecule: Implication for increased monocyte adhesion and migration in the CNS

Honghong Yao, Keejun Kim, Ming Duan, Teruo Hayashi, Minglei Guo, Susan Morgello, Alexander Prat, John Wang, Tsung Ping Su, Shilpa J Buch

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Human immunodeficiency virus (HIV)-associated increase in monocyte adhesion and trafficking is exacerbated by cocaine abuse. The underlying mechanisms involve cocaine-mediated up regulation 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 <r 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.

Original languageEnglish (US)
Pages (from-to)5942-5955
Number of pages14
JournalJournal of Neuroscience
Issue number16
StatePublished - Apr 20 2011


ASJC Scopus subject areas

  • Neuroscience(all)

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