Abstract
Cocaine dependence is associated with an increased risk of infectious diseases. The innate immune system triggers effector pathways to combat microbial pathogens through expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). It is not known whether cocaine alters the capacity of monocytes to respond to a bacterial challenge in humans. In cocaine-dependent volunteers and control subjects, we analyzed monocyte TNF-α and IL-6 expression at rest and in response to the bacterial ligand, lipopolysaccharide (LPS), over a 24-h period. In addition, the in vivo effects of cocaine (40 mg) versus placebo on monocyte expression of TNF-α and IL-6 were profiled over 48 h. Cocaine-dependent volunteers showed a decrease in the capacity of monocytes to express TNF-α and IL-6 compared with control subjects. Moreover, acute infusion of cocaine induced a further decline in the responsiveness of monocytes to LPS, which persisted after cocaine had cleared from the blood. Heart rate variability analyses showed that increases of sympathetic activity along with vagal withdrawal were associated with decreases in monocyte expression of TNF-α. Cocaine alters autonomic activity and induces protracted decreases in innate immune mechanisms. Targeting sympathovagal balance might represent a novel strategy for partial amelioration of impairments of innate immunity in cocaine dependence.
Footnotes
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This work was supported in part by National Institutes of Health Grants AA13239, DA16541, T32-MH19925, and M01 RR00827, the General Clinical Research Centers Program, and the Cousins Center for Psychoneuroimmunology.
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The principal investigator (M.R.I.) had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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The authors have no financial gain related to the outcome of this research, and there are no potential conflicts of interest.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.112797.
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ABBREVIATIONS: HIV, human immunodeficiency virus; LPS, lipopolysaccharide; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; TLR4, Toll-like receptor 4; IRB, Institutional Review Board; GCRC, UCLA General Clinical Research Center; mAb, monoclonal antibody; TNFrII, soluble TNF-α receptor; HF, high frequency; LF, low frequency; ANOVA, analysis of variance; ANCOVA, analysis of covariance; RU486, 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one.
- Received August 21, 2006.
- Accepted October 25, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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