Inhibition of virus replication by cocaine: Alterations in interferon production and calcium regulation
Grattendick, Kenneth John
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Previous studies have demonstrated cocaine to have a myriad of effects on the immune system. Depending on which component of the immune system is studied and the methods used, cocaine has been shown to possess both stimulatory and inhibitory effects. Cocaine has also been associated with an increase in the risk of developing infectious diseases, although a direct correlation has yet to be determined. The studies presented in this dissertation describe the effects of cocaine on host resistance to viral infections. Cocaine was found to possess antiviral properties in macrophages (Mø). L929 cells, and Madin Darby canine kidney (MDCK) cells in vitro. This effect was dose-dependent in all of these cells with 100 µg/ml exhibiting the maximal inhibition. A similar dose-dependent inhibition was observed in M0 exposed to norcocaine, a metabolite of cocaine. However, other metabolites did not show any effects on virus replication. Cocaine induced a time-dependent increase in the antiviral activity of Mǿ that was not reproduced in L929 or MDCK cells. On average, the antiviral effect of cocaine required approximately 24—48 hr to appear, indicating that the effect was not due to a direct interaction of cocaine and virus. Cocaine's inhibition of virus replication could be reversed by the addition of either antibodies to interferons (IFN) or calcium ionophores. An indication that the effect of cocaine was due to the secretion of an antiviral protein was found in experiments showing that the antiviral effect could be transferred from cells incubated with cocaine to unstimulated cells. This antiviral product was found to accumulate over time in the media and could be neutralized by the addition of anti-IFN. In studies to determine the direct effects of cocaine on IFN production, cocaine was found to induce a 2-3-fold increase in IFN secretion in both L929 cells and M0, with similar increases in IFN transcripts. Cocaine also demonstrated the ability to inhibit cell proliferation, an effect attributed to the production of IFN. Experiments were also conducted to determine if the antiviral effects of cocaine observed in vitro could be demonstrated in an animal model. C57B1/6 mice were infected with Influenzavirus A and given daily i.p. injections of 10 mg/kg cocaine or saline. Cocaine-injected mice were visibly less sick than control animals and had 50% less virus in their lungs, as determined by hemagglutination. This reduction in virus load was consistent with the previous in vitro experiments with cocaine. Because the addition of calcium ionophores had been demonstrated to reverse the antiviral effect of/« vitro cocaine exposure, studies were conducted to determine the effects of cocaine on intracellular calcium (Ca^2+) regulation. Mø incubated with 100 µg/ml cocaine for 48-72 hr demonstrated a 41% increase in steady-state Ca^2+ concentrations. This effect was observed when cells were assayed either in the presence or absence of extracellular Ca^2+ indicating an alteration in calcium regulation that was localized to either the cytoplasm or intracellular membranes. Studies on the mobilization of Ca^2+ showed an increase m ATP-induced Ca^2+ transients when Mø were incubated with cocaine. Calcium ATPase inhibitors reduced the calcium increases in cocaine-treated Mø, further supporting the hypothesis that cocaine was increasing calcium mobilization. This result also indicated that the mechanism by which cocaine altered intracellular Ca levels was most likely localized to the endoplasmic reticulum Ca^2+ -ATPases. In summary, cocaine was found to inhibit virus replication by increasing IFN production and altering cytoplasmic Ca^2+ levels.
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