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Abstract: Behavioral sensitization has been proposed to play an important role in addiction. Elucidation of the neural processes mediating sensitization may therefore lead to the development of new pharmacotherapeutic treatments. A large number of studies have examined sensitization to psychostimulants and morphine. In contrast, despite the prevalence of alcoholism, the neural processes underlying sensitization to ethanol have not been identified. The aim of the present study was to examine the role of different components of the dopamine system in sensitization to the locomotor stimulant effects of ethanol in DBA/2J mice. Sensitization was induced by administering ethanol [2g/kg intraperitoneally (ip)] before locomotor activity trials. Control groups received saline (12.5ml/kg ip) before each activity trial. The ability of the dopamine uptake inhibitors GBR 12909 (3.33–10.0mg/kg) and bupropion (20 and 30mg/kg) to cross-sensitize to ethanol was then examined. In addition, the effects of SKF 82958 (0.1–1.0mg/kg), a dopamine D1 (D1) receptor agonist, quinpirole (0.05 and 0.1mg/kg), a dopamine D2/D3 (D2/D3) receptor agonist, and a combination of SKF 82958 and quinpirole were examined. Cross-sensitization was observed between the dopamine uptake inhibitor GBR 12909 and ethanol. In contrast, the less selective uptake inhibitor bupropion did not exhibit cross-sensitization. Similarly, stimulation of D1 and D2/D3 receptors did not cause cross-sensitization even when the agonists were administered together. Taken together, these data suggest that sensitization to ethanol is associated with changes in the dopaminergic system. [Copyright &y& Elsevier]

Rationale: Behavioral sensitization has been accorded a central role in contemporary theories of drug addiction. Accordingly, a substantial effort has been made to determine the processes mediating sensitization to psychostimulants. However, few studies have examined the mechanisms underlying sensitization to ethanol. Objectives: Experiments were conducted to assess the role of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in expression of sensitization to ethanol's locomotor stimulant effects. Methods: Sensitization was induced in DBA/2 J mice by administering ethanol (2 g/kg) intraperitoneally (i.p.) before four activity trials. Control groups were given saline (12.5 ml/kg i.p.) before each activity trial. Subsequently, the effects of two NMDA receptor antagonists, MK-801 and ifenprodil, and two non-NMDA glutamate receptor antagonists, DNQX and GYKI 52466, were assessed on expression of the sensitized locomotor response. Results: MK-801 reduced the stimulant effects of ethanol and completely prevented expression of sensitization at doses exceeding 0.075 mg/kg. In contrast, although ifenprodil also reduced the stimulant effects of ethanol, the antagonist did not alter expression of sensitization. Non-NMDA glutamate antagonists were more consistent in their effects on sensitization. DNQX reduced the magnitude of the sensitized response at a low dose that did not alter the stimulant effects of ethanol. The more selective AMPA antagonist GYKI 52466 reduced the stimulant effects of ethanol and completely blocked expression of sensitization. Conclusions: The results provide initial evidence to suggest that both NMDA and non-NMDA glutamate receptors play a role in expression of sensitization to ethanol. Additional research will be required to elucidate the mechanisms underlying differences in the efficacy of glutamate antagonists. [ABSTRACT FROM AUTHOR]

Deep vein thrombosis (DVT), caused by alterations in venous homeostasis is the third most common cause of cardiovascular mortality; however, key molecular determinants in venous thrombosis have not been fully elucidated. Several lines of evidence indicate that DVT occurs at the intersection of dysregulated inflammation and coagulation. The enzyme ectonucleoside tri(di)phosphohydrolase (ENTPD1, also known as CD39) is a vascular ecto-apyrase on the surface of leukocytes and the endothelium that inhibits intravascular inflammation and thrombosis by hydrolysis of phosphodiester bonds from nucleotides released by activated cells. Here, we evaluated the contribution of CD39 to venous thrombosis in a restricted-flow model of murine inferior vena cava stenosis. CD39-deficiency conferred a >2-fold increase in venous thrombogenesis, characterized by increased leukocyte engagement, neutrophil extracellular trap formation, fibrin, and local activation of tissue factor in the thrombotic milieu. This was orchestrated by increased phosphorylation of the p65 subunit of NFκB, activation of the NLRP3 inflammasome, and interleukin-1β (IL-1β) release in CD39-deficient mice. Substantiating these findings, an IL-1β-neutralizing antibody attenuated the thrombosis risk in CD39-deficient mice. These data demonstrate that IL-1β is a key accelerant of venous thrombo-inflammation, which can be suppressed by CD39. CD39 inhibits in vivo crosstalk between inflammation and coagulation pathways, and is a critical vascular checkpoint in venous thrombosis. [ABSTRACT FROM AUTHOR]

Introduction: Deep vein thrombosis (DVT) and pulmonary embolism, together called venous thromboembolism, are the third most common cardiovascular disease in the U.S. and are growing in incidence and cost due to our aging population. While sterile inflammation plays a role in DVT, its precise function and mechanism have not been fully elucidated. Heme oxygenase-1 (HO-1) is an inducible enzyme responsible for the conversion of pro-inflammatory heme into iron and the anti-inflammatory molecules bilirubin and carbon monoxide (CO). The role of heme oxygenase-1 and its metabolic byproducts in venous thrombogenesis and innate immunity remains unknown. Methods and Results: We induced DVT by surgically restricting or interrupting (stasis) flow in the inferior vena cava (IVC) of HO-1+/- and WT mice. After 48 hours, HO-1+/- mice had a 50% increase in thrombus size when compared to WT mice following IVC stasis, but not flow restriction. Thrombi from HO-1 deficient mice demonstrated increased leukocyte recruitment to the thrombus and clot/vessel wall interface. HO-1+/- mice had greatly exaggerated thrombo-inflammatory signaling with increased fibrin, citrullinated histone 3, and IL-1β expression by immunoblot compared with WT DVT. As citrullination of histone 3 occurs during neutrophil extracellular trap (NET) formation, we examined the role of neutrophil activation in HO-1 mediated protection from DVT. Mature neutrophils isolated from HO-1+/- mice revealed a two-fold increase in both spontaneous and triggered NETosis in vitro. Conclusions: HO-1 may play an anti-inflammatory role in venous thrombogenesis. HO-1+/- mice have increased thrombogenesis with associated increased inflammatory cytokine expression and evidence of NETs. Studies are underway to define the key leukocyte populations present in murine venous thrombi to characterize their vascular cell-cell interactions. Further, additional downstream regulators are being explored as potential therapeutic targets in acute DVT formation and resolution. [ABSTRACT FROM AUTHOR]