In human addicts, craving and relapse are frequently evoked by the recall of memories connected to a drug experience. Established memories can become labile if recalled and can then be disrupted by several interfering events and pharmacological treatments, including inhibition of protein synthesis. Thus, reactivation of mnemonic traces provides an opportunity for disrupting memories that contribute to pathological states. Here, we tested whether the memory of a drug experience can be weakened by inhibiting protein synthesis after the reactivation of its trace. We found that an established morphine conditioned place preference (mCPP) was persistently disrupted if protein synthesis was blocked by either anisomycin or cycloheximide after the representation of a conditioning session. Unlike other types of memories, an established mCPP did not become labile after contextual recall, but required the concomitant re-experience of both the conditioning context and the drug. An established mCPP was disrupted after the conditioning session if protein synthesis was blocked selectively in the hippocampus, basolateral amygdala, or nucleus accumbens but not in the ventral tegmental area. This disruption seems to be permanent, because the preference did not return after further conditioning. Thus, established memories induced by a drug of abuse can be persistently disrupted after reactivation of the conditioning experience.

Rationale Previous studies have shown that chronic ethanol ingestion results in impaired alveolar macrophage function, increased TGF-β1 production, and decreased antioxidant availability. Similarly, alternative activation (M2 activation) of alveolar macrophages also induces TGF-β1 production and impairs macrophage function. However, the potential links between ethanol-induced alveolar macrophage derangements, M2 activation, TGF-β1 production signaling, and oxidant stress has yet to be examined. Objective We hypothesized that ethanol-induced oxidant stress and induction of TGF-β1 signaling results in alternative activation which subsequently impairs the phagocytic capacity of alveolar macrophages. Methods Primary rat alveolar macrophages and the alveolar macrophages cell line NR8383 was treated with 0.08% ethanol ± the antioxidant glutathione (GSH) or a TGF-β1 neutralizing antibody for 5 days. Outcome measures included TGF-β1 production, reactive oxygen species (ROS) production, phagocytic capacity, and expression of markers of M2 activation. Results Chronic ethanol treatment greatly decreased alveolar macrophage phagocytic function, increased ROS production, increased TGF-β1, and increased expression of markers of M2 activation. Glutathione supplementation and inhibition of TGF-β1 signaling during ethanol treatment prevented these alterations. Conclusions Ethanol treatment increased oxidant stress, TGF-β1 production, and alternative activation in NR8383 cells. However, GSH supplementation and ablation of TGF-β1 signaling prevented these effects. This suggested the ethanol-induced switch to a M2 phenotype was a result of decreased antioxidant availability and increased TGF-β1 signaling. Preventing ethanol-induced induction of alternative activation may improve alveolar macrophage function in alcoholic subjects and decrease the risk of respiratory infections.

Asthma, one of the most prevalent diseases affecting people worldwide, is a chronic respiratory disease characterized by heightened airway inflammation, airway hyperresponsiveness and airflow obstruction in response to specific triggers. While the specific mechanisms responsible for asthma are not well understood, changing environmental factors associated with urban lifestyles may underlie the increased prevalence of the disorder. Vitamin D is of particular interest in asthma since vitamin D concentrations decrease with increased time spent indoors, decreased exposure to sunlight, less exercise, obesity, and inadequate calcium intake. Additionally, a growing body of literature suggests that there is a relationship between vitamin D status and respiratory symptoms, presumably through immunomodulatory effects of vitamin D. This review discusses vitamin D as it relates to asthma across the age spectrum, with a focus on human studies.