Cigarette smoke and nicotine effects on brain proinflammatory responses and behavioral and motor function in HIV-1 transgenic rats

Abstract

Cognitive impairment in HIV-1 infection is associated with the induction of chronic proinflammatory responses in the brains of infected individuals. The risk of HIV-related cognitive impairment is increased by cigarette smoking, which induces brain inflammation in rodent models. To better understand the role of smoking and the associated immune response on behavioral and motor function in HIV infection, wild-type F344 and HIV-1 transgenic (HIV1Tg) rats were exposed to either smoke from nicotine-containing (regular) cigarettes, smoke from nicotine-free cigarettes, or to nicotine alone. The animals were then tested using the rotarod test (RRT), the novel object recognition test (NORT), and the open field test (OFT). Subsequently, brain frontal cortex from the rats was analyzed for levels of TNF-α, IL-1, and IL-6. On the RRT, impairment was noted for F344 rats exposed to either nicotine-free cigarette smoke or nicotine alone and for F344 and HIV1Tg rats exposed to regular cigarette smoke. Effects from the exposures on the OFT were seen only for HIV1Tg rats, for which function was worse following exposure to regular cigarette smoke as compared to exposure to nicotine alone. Expression levels for all three cytokines were overall higher for HIV1Tg than for F344 rats. For HIV1Tg rats, TNF-α, IL-1, and IL-6 gene expression levels for all exposure groups were higher than for control rats. All F344 rat exposure groups also showed significantly increased TNF-α expression levels. However, for F344 rats, IL-1 expression levels were higher only for rats exposed to nicotine-free and nicotine-containing CS, and no increase in IL-6 gene expression was noted with any of the exposures as compared to controls. These studies, therefore, demonstrate that F344 and HIV1Tg rats show differential behavioral and immune effects from these exposures. These effects may potentially reflect differences in the responsiveness of the various brain regions in the two animal species as well as the result of direct toxicity mediated by the proinflammatory cytokines that are produced by HIV proteins and by other factors that are present in regular cigarette smoke.

Keywords: Behavioral testing; Cigarettes; Cytokines; HIV-1; Smoking; Transgenic rat.

Figure 1

Analysis of HIV1Tg and F344 rat performance on a the rotarod test (total time on the rotating rod), b the novel object recognition test (mean percentage of time spent with an unfamiliar object), and c the openfield test (mean center time). The error bars represent the standard error of the mean values. *p < 0.05; **p < 0.01; ***p < 0.001 (adjusted for multiple comparisons using the Tukey test).

Figure 2

F344 and HIV1Tg rat exposure group versus control group frontal cortex proinflammatory cytokine gene expression. a Plots of TNF-α, IL-1, and IL-6 gene expression levels, analyzed by RT-PCR (N = 3 rats pergroup). b Comparison of cytokine gene expression levels. CIG = cigarettes; NIC = nicotine; *p < 0.05; **p < 0.01; ***p < 0.001 (adjusted for multiple comparisons using the Bonferroni correction).