Activation of microglia along with the release of inflammatory cytokines and oxidative factors often accompanies toxin-induced degeneration of substantia nigra pars compacta (SNc) dopamine (DA) neurons. Multiple toxin exposure may synergistically influence microglial-dependent DA neuronal loss and, in fact, pre-treatment with one toxin may sensitize DA neurons to the impact of subsequent insults. Thus, we assessed whether priming SNc neurons with the inflammatory agent, lipopolysaccharide (LPS), influenced the impact of later exposure to the pesticide, paraquat, which has been reported to provoke DA loss. Indeed, LPS infusion into the SNc sensitized DA neurons to the neurodegenerative effects of a series of paraquat injections commencing 2 days later. In contrast, LPS pre-treatment actually protected against some of neurodegenerative effects of paraquat when the pesticide was administered 7 days after the endotoxin. These sensitization and de-sensitization effects were associated with altered expression of reactive microglia expressing inducible immunoproteasome subunits, as well as variations of fibroblast growth factor and a time-dependent infiltration of peripheral immune cells. Circulating levels of the inflammatory cytokines, interleukin (IL)-6, IL-2, tumor necrosis factor-alpha and interferon-gamma were also time-dependently elevated following intra-SNc LPS infusion. These data suggest that inflammatory priming may influence DA neuronal sensitivity to subsequent environmental toxins by modulating the state of glial and immune factors, and these findings may be important for neurodegenerative conditions, such as Parkinson's disease (PD).