Evidence for Habitual and Goal-Directed Behavior Following Devaluation of Cocaine: A Multifaceted Interpretation of Relapse

BACKGROUND:Cocaine addiction is characterized as a chronically relapsing disorder. It is believed that cues present during self-administration become learned and increase the probability that relapse will occur when they are confronted during abstinence. However, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories of addiction posit that relapse-inducing cues cause relapse habitually or automatically, bypassing processing information related to the consequences of relapse. Alternatively, other theories hypothesize that relapse-inducing cues produce an expectation of the drug's consequences, designated as goal-directed relapse. Discrete discriminative stimuli signaling the availability of cocaine produce robust cue-induced responding after thirty days of abstinence. However, it is not known whether cue-induced responding is a goal-directed action or habit. METHODOLOGY/PRINCIPAL FINDINGS:We tested whether cue-induced responding is a goal-directed action or habit by explicitly pairing or unpairing cocaine with LiCl-induced sickness (n = 7/group), thereby decreasing or not altering the value of cocaine, respectively. Following thirty days of abstinence, no difference in responding between groups was found when animals were reintroduced to the self-administration environment alone, indicating habitual behavior. However, upon discriminative stimulus presentations, cocaine-sickness paired animals exhibited decreased cue-induced responding relative to unpaired controls, indicating goal-directed behavior. In spite of the difference between groups revealed during abstinent testing, no differences were found between groups when animals were under the influence of cocaine. CONCLUSIONS/SIGNIFICANCE:Unexpectedly, both habitual and goal-directed responding occurred during abstinent testing. Furthermore, habitual or goal-directed responding may have been induced by cues that differed in their correlation with the cocaine infusion. Non-discriminative stimulus cues were weak correlates of the infusion, which failed to evoke a representation of the value of cocaine and led to habitual behavior. However, the discriminative stimulus-nearly perfectly correlated with the infusion-likely evoked a representation of the value of the infusion and led to goal-directed behavior. These data indicate that abstinent cue-induced responding is multifaceted, dynamically engendering habitual or goal-directed behavior. Moreover, since goal-directed behavior terminated habitual behavior during testing, therapeutic approaches aimed at reducing the perceived value of cocaine in addicted individuals may reduce the capacity of cues to induce relapse

CD8+ T Cells and IFN-γ Mediate the Time-Dependent Accumulation of Infected Red Blood Cells in Deep Organs during Experimental Cerebral Malaria

Background: Infection with Plasmodium berghei ANKA (PbA) in susceptible mice induces a syndrome called experimental cerebral malaria (ECM) with severe pathologies occurring in various mouse organs. Immune mediators such as T cells or cytokines have been implicated in the pathogenesis of ECM. Red blood cells infected with PbA parasites have been shown to accumulate in the brain and other tissues during infection. This accumulation is thought to be involved in PbA–induced pathologies, which mechanisms are poorly understood. Methods and Findings: Using transgenic PbA parasites expressing the luciferase protein, we have assessed by real-time in vivo imaging the dynamic and temporal contribution of different immune factors in infected red blood cell (IRBC) accumulation and distribution in different organs during PbA infection. Using deficient mice or depleting antibodies, we observed that CD8 + T cells and IFN-c drive the rapid increase in total parasite biomass and accumulation of IRBC in the brain and in different organs 6–12 days post-infection, at a time when mice develop ECM. Other cells types like CD4 + T cells, monocytes or neutrophils or cytokines such as IL-12 and TNF-a did not influence the early increase of total parasite biomass and IRBC accumulation in different organs. Conclusions: CD8 + T cells and IFN-c are the major immune mediators controlling the time-dependent accumulation of P. berghei-infected red blood cells in tissues

The 5-Choice Continuous Performance Test: Evidence for a Translational Test of Vigilance for Mice

Attentional dysfunction is related to functional disability in patients with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and Alzheimer's disease. Indeed, sustained attention/vigilance is among the leading targets for new medications designed to improve cognition in schizophrenia. Although vigilance is assessed frequently using the continuous performance test (CPT) in humans, few tests specifically assess vigilance in rodents.We describe the 5-choice CPT (5C-CPT), an elaboration of the 5-choice serial reaction (5CSR) task that includes non-signal trials, thus mimicking task parameters of human CPTs that use signal and non-signal events to assess vigilance. The performances of C57BL/6J and DBA/2J mice were assessed in the 5C-CPT to determine whether this task could differentiate between strains. C57BL/6J mice were also trained in the 5CSR task and a simple reaction-time (RT) task involving only one choice (1CRT task). We hypothesized that: 1) C57BL/6J performance would be superior to DBA/2J mice in the 5C-CPT as measured by the sensitivity index measure from signal detection theory; 2) a vigilance decrement would be observed in both strains; and 3) RTs would increase across tasks with increased attentional load (1CRT task<5CSR task<5C-CPT).C57BL/6J mice exhibited superior SI levels compared to DBA/2J mice, but with no difference in accuracy. A vigilance decrement was observed in both strains, which was more pronounced in DBA/2J mice and unaffected by response bias. Finally, we observed increased RTs with increased attentional load, such that 1CRT task<5CSR task<5C-CPT, consistent with human performance in simple RT, choice RT, and CPT tasks. Thus we have demonstrated construct validity for the 5C-CPT as a measure of vigilance that is analogous to human CPT studies

Polyamide-Scorpion Cyclam Lexitropsins Selectively Bind AT-Rich DNA Independently of the Nature of the Coordinated Metal

Cyclam was attached to 1-, 2- and 3-pyrrole lexitropsins for the first time through a synthetically facile copper-catalyzed “click” reaction. The corresponding copper and zinc complexes were synthesized and characterized. The ligand and its complexes bound AT-rich DNA selectively over GC-rich DNA, and the thermodynamic profile of the binding was evaluated by isothermal titration calorimetry. The metal, encapsulated in a scorpion azamacrocyclic complex, did not affect the binding, which was dominated by the organic tail

PDGF and PDGF receptors in glioma

The family of platelet-derived growth factors (PDGFs) plays a number of critical roles in normal embryonic development, cellular differentiation, and response to tissue damage. Not surprisingly, as it is a multi-faceted regulatory system, numerous pathological conditions are associated with aberrant activity of the PDGFs and their receptors. As we and others have shown, human gliomas, especially glioblastoma, express all PDGF ligands and both the two cell surface receptors, PDGFR-α and -β. The cellular distribution of these proteins in tumors indicates that glial tumor cells are stimulated via PDGF/PDGFR-α autocrine and paracrine loops, while tumor vessels are stimulated via the PDGFR-β. Here we summarize the initial discoveries on the role of PDGF and PDGF receptors in gliomas and provide a brief overview of what is known in this field

Emergency Laparoscopic Repair for Incarcerated Ventral Hernia with Composite Mesh

Poster Presentation - Topic: Hernia: pogram no. P331OBJECTIVES: Laparoscopic repair has been widely used for uncomplicated ventral hernia as it is associated with fewer post-operative wound complications and a shorter hospital stay. We explored the safety of porcine collagen coated mesh (Parietex™Composite, COVIDIEN®) in emergency laparoscopic repair of acutely incarcerated ventral hernia. METHODS: Laparoscopic repair was attempted for patients who presented with acutely incarcerated ventral hernia. Those patients who had signs of peritonitis, who were hemodynamically unstable or who were anticipated to have extensive adhesions were excluded. Laparoscopy was performed and the adhesions were freed with sharp dissection, avoiding damage to the bowel. The mesh was placed with 5 cm overlap and secured with tackers. The outcomes of surgery were evaluated. RESULTS: Twelve patients who suffered from acutely incarcerated ventral underwent laparoscopic repair with Polypropylene-based composite mesh during the study period. The mean age of the patients was 64.6 years (33-91 years). The median ASA (American Society of Anesthetist) class was II. Six patients had incarcerated paraumbilical hernia and the rest of them were incisional hernia (n=5, 41.7%) and epigastric hernia (n =1, 8.3%). The incarcerated contents were small bowel (n=7), omentum (n=3), transverse colon (n=1) and urinary bladder (n=1). The mean area of defects was 34.9cm² (1-144cm²) and the mean operating time was 106.8 min (38-250 min). No intraoperative complication occurred and the mean hospital stay was 6 days (1-19 days). There was no mortality and two patients required post-operative Intensive Care Unit admission for monitoring. Five patients developed seroma and all subsided on conservative management. There was no other wound infection. CONCLUSIONS: Minimally invasive approach for acutely incarcerated ventral hernia is safe and feasible by using the porcine collagen coated polypropylene meshes. The outcomes of surgery are favorable and wound complications.can be reduced

Factors influencing the activation of the rapid response system for clinically deteriorating patients by frontline ward clinicians: a systematic review

Purpose: To synthesize factors influencing the activation of the rapid response system (RRS) and reasons for suboptimal RRS activation by ward nurses and junior physicians. Data sources: Nine electronic databases were searched for articles published between January 1995 and January 2016 in addition to a hand-search of reference lists and relevant journals. Study selection: Published primary studies conducted in adult general ward settings and involved the experiences and views of ward nurses and/or junior physicians in RRS activation were included. Data extraction: Data on design, methods and key findings were extracted and collated. Results of data synthesis: Thirty studies were included for the review. The process to RRS activation was influenced by the perceptions and clinical experiences of ward nurses and physicians, and facilitated by tools and technologies, including the sensitivity and specificity of the activation criteria, and monitoring technology. However, the task of enacting the RRS activations was challenged by seeking further justification, deliberating over reactions from the rapid response team and the impact of workload and staffing. Finally, adherence to the traditional model of escalation of care, support from colleagues and hospital leaders, and staff training were organizational factors that influence RRS activation. Conclusion: This review suggests that the factors influencing RRS activation originated from a combination of socio-cultural, organizational and technical aspects. Institutions that strive for improvements in the existing RRS or are considering to adopt the RRS should consider the complex interactions between people and the elements of technologies, tasks, environment and organization in healthcare settings