Alteration of immune responses by cocaine: Cytokines and reactive nitrogen intermediates

In recent years cocaine abuse has reached epidemic proportions. The use of cocaine, like many other drugs of abuse, has been shown to have immunomodulatory consequences. However, the effects of cocaine on the immune system have not been thoroughly examined.

The macrophage (M0) plays a central role in the regulation of inflammatory responses, antigen presentation, and is an important non-specific first line of defense against incoming pathogens. In the present studies, the immunomodulatory effects of cocaine on certain aspects of M0 functions were examined. Cocaine was administered to experimental mice and/or M0 were exposed to cocaine or one of its metabolites in vitro. Experiments were conducted to determine the effects of cocaine on the ability of M0 to produce cytokines and reactive nitrogen intermediates (RNI). A novel method of cytokine induction using a mannose receptor ligand was also developed. Mannosylated bovine serum albumin (M-BS A) was administered to a variety of cell types including M0, and shown to induce cytokine secretion. M0 from cocaine-injected mice displayed a reduced ability to secrete proinflammatory cytokines when stimulated with M-BSA. This effect was also demonstrated by M0 exposed to cocaine in vitro. However, due to the acute nature of cocaine's effects, it had no effect on the secretion of regulatory cytokines. Cytokine mRNA levels were unaffected by cocaine exposure, suggesting the mechanism of inhibition involved attenuation of cytokine secretion, but not transcription. In vivo cocaine administration, but not in vitro cocaine exposure, caused inhibition of RNI in M0. In vitro exposure to the metabolite norcocaine inhibited nitrite production, suggesting a possible in vivo mechanism. iNOS levels were analyzed via Western blot, showing that iNOS protein levels were unaffected by norcocaine. The mechanism of inhibition appeared to be through the attenuation of iNOS enzymatic activity.

Collectively, these studies indicate that cocaine impairs M0 proinflammatory activity and has the ability to cause immune system compromise. These studies suggest that the immunoregulatory effects of cocaine may lead to increased instances of infectious disease in drug addict populations.