RT Journal Article
SR Electronic
T1 κ-Opioid Receptor Ligands Inhibit Cocaine-Induced HIV-1 Expression in Microglial Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 600
OP 606
DO 10.1124/jpet.103.060160
VO 309
IS 2
A1 Genya Gekker
A1 Shuxian Hu
A1 Mark P. Wentland
A1 Jean M. Bidlack
A1 James R. Lokensgard
A1 Phillip K. Peterson
YR 2004
UL http://jpet.aspetjournals.org/content/309/2/600.abstract
AB Cocaine abuse has been implicated as a cofactor in human immunodeficiency virus (HIV)-1-associated dementia (HAD). In this study, we tested the hypothesis that exposure of microglial cells, the resident macrophages of the brain, to cocaine would potentiate HIV-1 expression. Because κ-opioid receptor (KOR) agonists have been shown to suppress neurochemical and neurobehavioral responses to cocaine and to inhibit HIV-1 expression in microglial cell cultures, we also postulated that KOR ligands would inhibit cocaine-induced potentiation of HIV-1 expression. Human microglial cells were infected with HIV-1SF162, an R5 isolate, and viral expression was quantified by measurement of p24 antigen in culture supernatants. Treatment of microglia with the KOR agonists trans-(±)-3,4-dichlor-N-methyl-N-(2[1-pyrrolidnyl])benzeneacetamide methanesulfonate and 8-carboxamidocyclazocine inhibited viral expression (maximal suppression of 42 and 48%, respectively). Consistent with the hypotheses, treatment of microglia with cocaine promoted HIV-1 expression (maximal enhancement of 54%), and pretreatment of microglia with these KOR agonists as well as with the KOR-selective antagonist nor-binaltorphimine abrogated cocaine-induced potentiation of viral expression. Results of flow cytometry studies suggested that the mechanism whereby KOR ligands inhibit cocaine's stimulatory effect on viral expression involves the suppression of cocaine-induced activation of extracellular signal-regulated kinase1/2, thereby blunting cocaine-enhanced up-regulation of the HIV-1 entry chemokine coreceptor CCR5. The findings of this study suggest that in addition to its neurotoxic effects, cocaine could foster development of HAD by potentiating viral expression in the brain and that this phenomenon is inhibited by KOR ligands. The American Society for Pharmacology and Experimental Therapeutics