There is high incidence of bacterial, viral, and fungal opportunistic infections among long-term heroin users. Our laboratory was the first to demonstrate that, remarkably, environmental stimuli paired with heroin administration acquire heroin-like immunomodulatory properties as a result of associative learning processes. Thus, the detrimental health consequences of opiates can be conditioned to environmental stimuli predictive of drug administration. The proposed studies are the first to characterize the role of dopamine in the nucleus accumbens and amygdala in the conditioned immunomodulatory effects of heroin. The studies will assess the effects of intra-nucleus accumbens and intra-amygdala administration of dopamine receptor antagonists on heroin-conditioned alterations in the expression of proinflammatory immune responses. Lipopolysaccharide (LPS) will be used to challenge the immune system. LPS is an immunogenic component of Gram-negative bacteria that induces robust proinflammatory immune responses, and it is well established that heroin-paired stimuli attenuate the expression of these immune responses. Specific Aim I tests the hypothesis that stimulation of dopamine receptors in the nucleus accumbens is necessary for the expression of conditioned opioid-induced reductions in the production of in vivo proinflammatory cytokines and nitric oxide. The proposed investigations provide a comprehensive assessment of the role of nucleus accumbens dopamine receptors in the expression of heroin-conditioned immunomodulation. Specific Aim II tests the hypothesis that dopamine receptor stimulation in the amygdala is necessary to produce the expression of conditioned opioid-induced reductions in the in vivo proinflammatory cytokines and nitric oxide. The proposed investigations determine the role of amygdalar dopamine receptors in the expression of heroin-conditioned immunomodulation using selective dopaminergic receptor antagonists. Specific Aim III tests the hypothesis that sequential information processing by the amygdala and nucleus accumbens is necessary for heroin-induced conditioned immunomodulation. The proposed experiments will evaluate whether communication between the amygdala and nucleus accumbens is necessary for expression of heroin-induced conditioned immunomodulation. These experiments are especially important for they are the first to examine systems-level interaction between brain regions mediating this important function. Collectively, these studies provide new insights into the neuroanatomical substrates and dopamine receptor mechanisms of conditioned opioid/immune interactions, and make important advancements in our understanding of the health consequences of opioid use.