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Cocaine has been demonstrated to have a number of different effects on immune cell functions. We have reported alterations of cellular functions by macrophages (Mphi) exposed to cocaine in vitro, including the inhibition of mouse hepatitis virus replication. Here, we present evidence that cocaine stimulates the secretion of an antiviral product that is neutralized by anti-interferon (anti-IFN). A dose-dependent increase in the secretion of IFN by both Mphi and L929 cells incubated with cocaine, with a concomitant decrease in virus replication, is also reported. The increase in IFN secretion was most pronounced when cells were cultured in the presence of the IFN inducer poly(I.C). The effect of cocaine on IFN production was found to be primarily at the transcript level in both Mphi and L929 cells. These findings further support our previous research demonstrating an antiviral activity of cocaine in vitro. The relevance of this activity to viral infections in general remains to be determined.

Cocaine has been shown to have a number of diverse effects on the immune system. The current investigators have previously demonstrated an inhibitory effect of cocaine on murine hepatitis virus replication in peritoneal macrophages in vitro. The present study was undertaken to examine the effects of cocaine on influenza virus replication and to further characterize that effect in an animal model. Cocaine was capable of inducing a dose-dependent reduction in influenza PR-8 replication using MDCK cells in vitro. Concentrations of 100 microg/ml caused a 50% reduction of virus. To further characterize the effect in vivo, C57Bl/6 mice infected with influenza PR-8 by intranasal instillation were given daily ip injections of 10 mg/kg cocaine just prior to and for 4 days after exposure to influenza. Lungs from mice exposed to cocaine had viral titers that were reduced approximately 50% compared to controls as demonstrated by hemagglutination titers. Additional studies suggest that this reduction appears to be caused by an increase of cocaine-induced interferon.

Our previous studies have demonstrated a number of effects of cocaine on macrophage (M phi) functions. The present studies were initiated to ascertain the effects of cocaine on virus production in vitro. C57BL/6 mice were injected intraperitoneally with thioglycollate broth, and the peritoneal M phi collected 4 days later were cultured in 96-well microtiter plates as continuous monolayers. Various concentrations of cocaine were incubated with M phi for up to 5 days. Mouse hepatitis virus (MHV) was added to these cultures, which was followed by a methyl cellulose overlay. Cocaine caused a dose-dependent inhibition of viral plaques after 48 hr of incubation. The inhibitory activity was transferable to fresh cultures of M phi, inhibiting both plaque size and number. Specific polyclonal antibodies to alpha + beta-interferon but not tumor necrosis factor or transforming growth factor-beta partially reversed the inhibition of both plaque size and plaque number. It appears that MHV induced interferon in cultured M phi, an effect that was enhanced by cocaine. Since cocaine has been reported to interfere with calcium mobilization, studies were done using ionomycin, a calcium ionophore, in order to reverse possible effects on intracellular calcium that could affect virus production. The presence of ionomycin completely reversed the inhibition of virus production by cocaine. The antiviral effects of cocaine appear to be caused by modulation of intracellular calcium and, to a lesser extent, by the enhancement of interferon production.

Cocaine, a naturally occurring alkaloid, is known to affect the immune system. The present authors have demonstrated that peritoneal macrophages, isolated from mice injected with cocaine, have an increased capacity for the production of reactive oxygen intermediates (ROI) and a decreased capacity for the production of reactive nitrogen intermediates (RNI). The present studies were done to determine the effects of certain cocaine metabolites on the induction of ROI and RNI by peritoneal macrophages. C57BL/6 mice were injected i.p. with either saline or 5 mg/kg of one of the following: cocaine, norcocaine, benzoylecgonine, ecgonine methyl ester HCl or ecgonine HCl. The ROI were measured using a chemiluminescence assay and the RNI were measured as nitrite secretion following exposure of isolated M phi to interferon gamma and LPS. Isolated peritoneal M phi from mice injected i.p. with cocaine, norcocaine and benzoylecgonine exhibited an increase in the production of ROI and a concomitant decrease in the production of RNI. However, injections of either ecgonine methylester HCl or ecgonine HCl had no effect on the induction of either ROI or RNI by murine peritoneal M phi. The cocaine metabolites, norcocaine and benzoylecgonine, have been reported to cause hepatic and/or cerebral toxicity. The present study also demonstrated that injection of these metabolites in vivo, also altered M phi functions which were measured in vitro.

The effects of cocaine on the respiratory burst (RB) and the phagocytic activity of murine macrophages (M phi) were studied. C57BL/6 mice were injected intraperitoneally with various concentrations of cocaine or appropriate vehicle. Peritoneal and alveolar M phi were isolated from mice and cultured in vitro. Both alveolar and peritoneal M phi from cocaine-exposed mice exhibited an increase in the RB when compared with M phi from saline-injected controls. This increase in the RB was apparent 60 min after injection and persisted for at least 48 hr. Injection of the cocaine metabolites, ecgonine methyl ester hydrochloride and ecgonine hydrochloride, did not affect the RB. The increase in the RB was correlated with an increase in phagocytosis of opsonized zymosan in vitro. However, an in vivo phagocytic assay using mice injected ip with cocaine, which was subsequently followed by sheep erythrocytes, demonstrated the opposite effect. Fewer peritoneal M phi from cocaine-injected mice were observed with ingested erythrocytes. These data underscore the complex effects of cocaine on M phi functions.

The present study describes the inhibition of macrophage-mediated cytotoxicity (MMC) by cocaine and suggests a possible mechanism. Mice (C57BL/6) were injected i.p. with cocaine. At various intervals after exposure to cocaine, peritoneal macrophages (M phi) were removed, cultured in the presence of interferon gamma and LPS, then incubated with 51Cr labeled target cells. A single injection of > or = 10 mg/kg cocaine was sufficient to inhibit cytotoxicity to P815 cells. This inhibition was evident 3 h after exposure to cocaine and could still be demonstrated 24 h later. Since reactive nitrogen intermediates (RNI) have been reported to be one of the major mechanisms by which M phi kill, the amounts of NO2- produced by M phi from cocaine-injected animals were compared with that produced by equivalent controls. Cocaine reduced the level of NO2- in a dose-dependent manner which correlated with MMC. There was a significant reduction in NO2- produced by activated M phi, 3 h after i.p. injection of cocaine but not at 24 h, using > or = 5 mg/kg. At 12 h there were differences between M phi from control animals and animals receiving > or = 10 mg/kg cocaine. By 24 h there were no differences between control and cocaine-injected animals even at the highest dose employed (25 mg/kg). These results suggest that cocaine reduces the killing ability of murine M phi through a temporary reduction of RNI.

Cocaine is a central nervous stimulant with a major potential for abuse. It is used clinically as a local anesthetic and vasoconstrictor. The effects of cocaine on the immune system have not been studied in depth. In this study, we have investigated the effects of cocaine on the respiratory burst (RB) of murine macrophages (M phi). The RB was measured by determining the increase in chemiluminescence. Both peritoneal and alveolar M phi were isolated from cocaine-exposed mice and saline-exposed controls. Cocaine was administered by the intraperitoneal, intravenous, and intramuscular route. Both peritoneal and alveolar M phi from cocaine-exposed mice showed an increase in chemiluminescence when compared with M phi from matched controls. This effect was seen as early as one hour after cocaine exposure and lasted for up to 48 hours. Intraperitoneal injection of cocaine metabolites did not affect the RB. Macrophages exposed to cocaine in vitro failed to respond by an increase in RB. These findings indicate that cocaine induces the production of reactive oxygen intermediates (ROI) and suggests possible changes in M phi functions.

Background: Earlier reports of cocaine-associated cerebral vasculitis have been based primarily on angiographic findings without pathological verification., Case Description: We present a case of acute encephalopathy following intravenous and intranasal administration of cocaine. Brain biopsy revealed vascular changes involving primarily small arteries. Findings included lymphocytic infiltration, endothelial thickening, and deposition of proteinaceous amorphous material within and around vessel walls., Conclusions: These abnormalities are consistent with pathological features of arteritis previously reported in association with amphetamine and multiple-drug abuse. Vasospasm-induced changes are an alternative explanation for the vascular picture seen in this case. The patient made modest improvement with high-dose intravenous steroids.