Cocaine abuse hastens the neurodegeneration often associated with advanced HIV-1 infection. The mechanisms, in part, revolve around the neuroinflammatory processes mediated by the chemokine monocyte chemotactic protein-1 (MCP-1/ CCL2). Understanding factors that modulate MCP-1 and, in turn, facilitate monocyte extravasation in the brain is thus of paramount importance. We now demonstrate that cocaine induces MCP-1 in rodent microglia through translocation of the sigma receptor to the lipid raft microdomains of the plasma membrane.Sequential activation of Src, mitogenactivated protein kinases (MAPKs), and phosphatidylinositol-3 kinase (PI3K)/Akt and nuclear factor B (NF-B) pathways resulted in increased MCP-1 expression. Furthermore, conditioned media from cocaine-exposed microglia increased monocyte transmigration, and thus was blocked by antagonists for CCR2 or sigma receptor. These findings were corroborated by demonstrating increased monocyte transmigration in mice exposed to cocaine, which was attenuated by pretreatment of mice with the sigma receptor antagonist. Interestingly, cocaine-mediated transmigratory effects were not observed in CCR2 knockout mice. We conclude that cocaine-mediated induction of MCP-1 accelerates monocyte extravasation across the endothelium. Understanding the regulation of MCP-1 expression and functional changes by cocaine/sigma receptor system may provide insights into the development of potential therapeutic targets for HIV-1-associated neurocognitive disorders.
IntroductionHIV-1-associated neurocognitive disorders (HANDs) remain a common complication of viral infection despite the advent of antiretroviral therapies (ARTs). One contributing factor is the use of illicit drugs, including but not limited to cocaine. The mechanism by which cocaine augments HANDs has been the subject of intense research. 1,2 One possibility rests in the idea that the drug can "open" the blood brain barrier (BBB), which, in turn, can facilitate transmigration of bloodborne inflammatory monocytes into the brain. 3,4 Although considerable efforts have been made to best understand the cellular and molecular mechanisms underlying the effects of cocaine on proinflammatory factor secretion and BBB function, 5 there exists a paucity of information on the mechanisms by which cocaine influences chemokine secretion and cell migration into and within the central nervous system (CNS).Common neuropathologic correlates for HANDs include BBB disruption, glial activation, neuroinflammation (proinflammatory factors and chemokines), viral replication, and neuronal aberrations. The key factor mediating monocyte-macrophage transmigration across the BBB is the CC chemokine, monocyte chemoattractant protein-1 (MCP-1/CCL2), 6 which mediates its effects by binding to its cognate receptor CCR2. 7 Moreover, the best correlate for cognitive impairment remains the numbers of immune competent brain mononuclear phagocytes (MPs; bloodborne macrophages and microglia). Exploration of mechanisms that modulate MCP-1 in the brain is thus...