Are cocaine-seeking “habits” necessary for the development of addiction-like behavior in rats?

Drug self-administration models of addiction typically require animals to make the same response (e.g., a lever-press or nose-poke) over and over to procure and take drugs. By their design, such procedures often produce behavior controlled by stimulus-response (S-R) habits. This has supported the notion of addiction as a “drug habit”, and has led to considerable advances in our understanding of the neurobiological basis of such behavior. However, for addicts to procure drugs, like cocaine, often requires considerable ingenuity and flexibility in seeking behavior, which, by definition, precludes the development of habits. To better model drug-seeking behavior in addicts we first developed a novel cocaine self-administration procedure (the Puzzle Self-Administration Procedure; PSAP) that required rats to solve a new puzzle every day to gain access to cocaine, which they then self-administered on an Intermittent Access (IntA) schedule. Such daily problem-solving precluded the development of S-R seeking habits. We then asked whether prolonged PSAP/IntA experience would nevertheless produce ‘symptoms of addiction’. It did, including escalation of intake, sensitized motivation for drug, continued drug use in the face of adverse consequences and very robust cue-induced reinstatement of drug-seeking, especially in a subset of ‘addiction-prone’ rats. Furthermore, drug-seeking behavior continued to require dopamine neurotransmission in the core of the nucleus accumbens (but not the dorsolateral striatum). We conclude that the development of S-R seeking habits is not necessary for the development of cocaine addiction-like behavior in rats

Enterprise Strategic Analysis and Transformation ESAT

Organizations operate today in a heightened competitive environment in which change is the only certainty. The adage of when in doubt restructure brought about by reengineering, and the turbulence of mergers, acquisitions, and divestitures, has resulted in organizations with often impenetrable functional silos. The challenges bought forth by globalization, schedule compression, cost constraints, time to market pressures, capability differentials in the supplier base, growing shortages of human capital and pressures from stockholders, requires organizations to take a more holistic approach to transformation. The Enterprise Strategic Analysis and Transformation (ESAT) methodology provides a means for the senior leadership team to understand their enterprise, create an actionable vision for the future, plan the transformation and govern the execution

Enterprise Strategic Analysis and Transformation Facilitator's Guide

This document is intended as a guide for ESAT facilitators. It provides an overview of the ESAT process, but it is assumed that all facilitators are comfortably familiar with the process as described in the ESAT Guide document and the ESAT KEE Modules (both instructional and facilitization)

Rapid induction of dopamine sensitization in the nucleus accumbens shell induced by a single injection of cocaine

Repeated intermittent exposure to cocaine results in the neurochemical sensitization of dopamine (DA) transmission within the nucleus accumbens (NAc). Indeed, the excitability of DA neurons in the ventral tegmental area (VTA) is enhanced within hours of initial psychostimulant exposure. However, it is not known if this is accompanied by a comparably rapid change in the ability of cocaine to increase extracellular DA concentrations in the ventral striatum. To address this question we used fast-scan cyclic voltammetry (FSCV) in awake-behaving rats to measure DA responses in the NAc shell following an initial intravenous cocaine injection, and then again 2-hours later. Both injections quickly elevated DA levels in the NAc shell, but the second cocaine infusion produced a greater effect than the first, indicating sensitization. This suggests that a single injection of cocaine induces sensitization-related plasticity very rapidly within the mesolimbic DA system

Pennsylvania Folklife Vol. 30, No. 2

• A Search for the Origin of the Pennsylvania Barn • A Forebay Bank Barn in Texas • The Swiss Bank House Revisited: Messerschmidt-Dietz Cabin • Paul R. Wieand, Lehigh County Folk Artist • Aldes un Neies / Old & Newhttps://digitalcommons.ursinus.edu/pafolklifemag/1090/thumbnail.jp

Rats that sign-track are resistant to Pavlovian but not instrumental extinction

Individuals vary in the extent to which they attribute incentive salience to a discrete cue (conditioned stimulus; CS) that predicts reward delivery (unconditioned stimulus; US), which results in some individuals approaching and interacting with the CS (sign-trackers; STs) more than others (goal-trackers; GTs). Here we asked how periods of non-reinforcement influence conditioned responding in STs vs. GTs, in both Pavlovian and instrumental tasks. After classifying rats as STs or GTs by pairing a retractable lever (the CS) with the delivery of a food pellet (US), we introduced periods of non-reinforcement, first by simply withholding the US (i.e., extinction training; experiment 1), then by signaling alternating periods of reward (R) and non-reward (NR) within the same session (experiments 2 and 3). We also examined how alternating R and NR periods influenced instrumental responding for food (experiment 4). STs and GTs did not differ in their ability to discriminate between R and NR periods in the instrumental task. However, in Pavlovian settings STs and GTs responded to periods of non-reward very differently. Relative to STs, GTs very rapidly modified their behavior in response to periods of non-reward, showing much faster extinction and better and faster discrimination between R and NR conditions. These results highlight differences between Pavlovian and instrumental extinction learning, and suggest that if a Pavlovian CS is strongly attributed with incentive salience, as in STs, it may continue to bias attention toward it, and to facilitate persistent and relatively inflexible responding, even when it is no longer followed by reward

The HST/ACS Coma Cluster Survey. II. Data Description and Source Catalogs

The Coma cluster was the target of a HST-ACS Treasury program designed for deep imaging in the F475W and F814W passbands. Although our survey was interrupted by the ACS instrument failure in 2007, the partially completed survey still covers ~50% of the core high-density region in Coma. Observations were performed for 25 fields that extend over a wide range of cluster-centric radii (~1.75 Mpc) with a total coverage area of 274 arcmin^2. The majority of the fields are located near the core region of Coma (19/25 pointings) with six additional fields in the south-west region of the cluster. In this paper we present reprocessed images and SExtractor source catalogs for our survey fields, including a detailed description of the methodology used for object detection and photometry, the subtraction of bright galaxies to measure faint underlying objects, and the use of simulations to assess the photometric accuracy and completeness of our catalogs. We also use simulations to perform aperture corrections for the SExtractor Kron magnitudes based only on the measured source flux and half-light radius. We have performed photometry for ~73,000 unique objects; one-half of our detections are brighter than the 10-sigma point-source detection limit at F814W=25.8 mag (AB). The slight majority of objects (60%) are unresolved or only marginally resolved by ACS. We estimate that Coma members are 5-10% of all source detections, which consist of a large population of unresolved objects (primarily GCs but also UCDs) and a wide variety of extended galaxies from a cD galaxy to dwarf LSB galaxies. The red sequence of Coma member galaxies has a constant slope and dispersion across 9 magnitudes (-21<M_F814W<-13). The initial data release for the HST-ACS Coma Treasury program was made available to the public in 2008 August. The images and catalogs described in this study relate to our second data release.Comment: Accepted for publication in ApJS. A high-resolution version is available at http://archdev.stsci.edu/pub/hlsp/coma/release2/PaperII.pd

Requirement of argininosuccinate lyase for systemic nitric oxide production

Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases

A study of the structure–activity relationship of GABAA–benzodiazepine receptor bivalent ligands by conformational analysis with low temperature NMR and X-ray analysis

The stable conformations of GABAA-benzodiazepine receptor bivalent ligands were determined by low temperature NMR spectroscopy and confirmed by single crystal X-ray analysis. The stable conformations in solution correlated well with those in the solid state. The linear conformation was important for these dimers to access the binding site and exhibit potent in vitro affinity and was illustrated for α5 subtype selective ligands. Bivalent ligands with an oxygen-containing linker folded back upon themselves both in solution and the solid state. Dimers which are folded do not bind to Bz receptors

Impact of electronic medical record on physician practice in office settings: a systematic review

<p>Abstract</p> <p>Background</p> <p>Increased investments are being made for electronic medical records (EMRs) in Canada. There is a need to learn from earlier EMR studies on their impact on physician practice in office settings. To address this need, we conducted a systematic review to examine the impact of EMRs in the physician office, factors that influenced their success, and the lessons learned.</p> <p>Results</p> <p>For this review we included publications cited in Medline and CINAHL between 2000 and 2009 on physician office EMRs. Studies were included if they evaluated the impact of EMR on physician practice in office settings. The Clinical Adoption Framework provided a conceptual scheme to make sense of the findings and allow for future comparison/alignment to other Canadian eHealth initiatives.</p> <p>In the final selection, we included 27 controlled and 16 descriptive studies. We examined six areas: prescribing support, disease management, clinical documentation, work practice, preventive care, and patient-physician interaction. Overall, 22/43 studies (51.2%) and 50/109 individual measures (45.9%) showed positive impacts, 18.6% studies and 18.3% measures had negative impacts, while the remaining had no effect. Forty-eight distinct factors were identified that influenced EMR success. Several lessons learned were repeated across studies: (a) having robust EMR features that support clinical use; (b) redesigning EMR-supported work practices for optimal fit; (c) demonstrating value for money; (d) having realistic expectations on implementation; and (e) engaging patients in the process.</p> <p>Conclusions</p> <p>Currently there is limited positive EMR impact in the physician office. To improve EMR success one needs to draw on the lessons from previous studies such as those in this review.</p