Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation

Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.     

Challenge-induced plasma exudation and mucinous secretion in human airways

Secretion of mucins and exudation of plasma are distinct processes of importance to innate immunity and inflammatory disease. Yet, little is known about their relation in human airways. The objective of the present study was to use the human nasal airway to determine mucinous secretion and plasma exudation in response to common challenge agents and mediators. Ten healthy volunteers were subjected to nasal challenge-lavage procedures. Thus, the nasal mucosa was exposed to increasing doses of histamine (40 and 400 microg ml(-1)), methacholine (12.5 and 25 mg) and capsaicin (30 and 300 ng ml(-1)). Fucose was selected as a global marker of mucinous secretion and alpha(2)-macroglobulin as an index of exudation of bulk plasma. All challenge agents increased the mucosal output of fucose to about the same level (P<0.01-0.05). Once significant secretion had been induced the subsequently increased dose of the challenge agent, in the case of histamine and methacholine, failed to further increase the response. Only histamine increased the mucosal output of alpha(2)-macroglobulin (P<0.01). We conclude that prompt but potentially rapidly depleted mucinous secretion is common to different kinds of airway challenges, whereas inflammatory histamine-type mediators are required to produce plasma exudation. Along with the acknowledged secretion of mucins, a practically non-depletable, pluripotent mucosal output of plasma emerges as an important component of the innate immunity of human airways.     

A novel modification of the Thrombelastograph assay, isolating platelet function, correlates with optical platelet aggregation

Flow cytometry, singlet platelet counting, and optical aggregation have been used to monitor clopidogrel and glycoprotein IIb/IIIa (GPIIb/IIIa) platelet antagonists. Optical aggregation is considered the gold standard, but neither it nor flow cytometry is convenient in larger-scale clinical studies or point-of-care systems. Singlet platelet counting, a point-of-care assay correlated with optical platelet aggregation, only provides a measurement of platelet function at a single point in time. The Thrombelastograph is used to assay whole blood for thrombin-generated maximal clot-shear elasticity, referred to as the maximal amplitude (MA). Although platelet dysfunction, thrombocytopenia, and the in vitro effect of strong inhibitors such as IIb/IIIa antagonists can be observed, with thrombin generation milder platelet inhibitors cannot be assessed. We modified the Thromboelastograph assay, using reptilase and factor XIIIa, to form a clot, without thrombin generation, in heparinized whole blood. The resulting clot MA is dependent on added platelet agonists such as ADP or arachidonic acid, is sensitive to platelet antagonists, and provides a continuous measure of platelet function more analogous and better correlated with optical aggregation. This novel modification of the Thromboelastograph assay should prove to be a useful point-of-care whole-blood assay with which to monitor the effects of GPIIb/IIIa, ADP, and thromboxane A(2)-receptor-inhibiting drugs in patients.     

The Addenbrooke’s Cognitive Examination-Revised accurately detects cognitive decline in Huntington’s disease

Cognitive features, which begin before manifestation of the motor features, are an integral part of Huntington’s disease and profoundly affect quality of life. A number of neuropsychological batteries have been used to assess this aspect of the condition, many of which are difficult to administer and time consuming, especially in advanced disease. We, therefore, investigated a simple and practical way to monitor cognition using the Addenbrooke’s Cognitive Examination-Revised (ACE-R) in 126 manifest Huntington’s disease patients, 28 premanifest gene carriers and 21 controls. Using this test, we demonstrated a selective decrease in phonemic, but not semantic, fluency in premanifest participants Cognitive decline in manifest Huntington’s disease varied according to disease severity with extensive cognitive decline observed in early-stage Huntington’s disease patients, indicating that this would be an optimal stage for interventions designed to halt cognitive decline, and lesser changes in the advanced cases. We next examined cognitive performance in patients prescribed antidopaminergic drugs as these drugs are known to decrease cognition when administered to healthy volunteers. We paradoxically found that these drugs may be beneficial, as early-stage Huntington’s disease participants in receipt of them had improved attention and Mini-Mental State Examination scores. In conclusion, this is the first study to test the usefulness of the ACE-R in a Huntington’s disease population and demonstrates that this is a brief, inexpensive and practical way to measure global cognitive performance in clinical practice with potential use in clinical trials.     

Perceived threat in compliance and adherence research

Within the broader agenda of adherence research, health beliefs have been identified as being significant predictors of adherence. Specifically, perceived threat as a health belief has received considerable attention in compliance and adherence research from multiple perspectives in multiple patient populations. The purpose of this paper is to analyze the concept of perceived threat as it relates to treatment adherence through a series of perspectives: conceptual, methodological, and empirical. Analysis of the literature reveals that there is lack of consistency in operationalization of perceived threat as it relates to treatment adherence. Perceived threat is most commonly cited in studies that focus on health beliefs or utilize a stress and coping paradigm. Instruments have been developed with items that measure perceived threat. Measures of threat occur primarily through uni-dimensional measures that do not reflect the inter-relatedness of the threat experience to personal and contextual factors. Future research examining perceived threat from a cognitive appraisal perspective, where both primary and secondary appraisals can be examined, may provide additional insight into factors affecting treatment adherence.     

The role of therapist adherence,therapist competence,and alliance in predicting outcome of individual drug counseling: Results from the National Institute Drug Abuse Collaborative Cocaine Treatment Study

Abstract

This study tested hypotheses related to linear and curvilinear relations among adherence, competence, and outcome and interactions of these effects with the quality of the therapeutic alliance among patients (N=95) who received individual drug counseling as part of the National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Results support a hypothesized curvilinear relation between adherence and outcome as well as an interaction between this curvilinear effect and alliance early in treatment. For patients with a strong therapeutic alliance, counselor adherence to the treatment model was essentially irrelevant to treatment outcome. When the alliance was weaker, by contrast, a moderate (vs. high or low) level of counselor adherence was associated with the best outcome. The current results suggest that studies of the relation between therapist's adherence to models of treatment and outcome may need to take into account the complex moderating effect of therapeutic alliance.

Diese Studie testete Hypothesen bezüglich linearer und kurvilinearer Beziehungen zwischen vorgabegetreuem Vorgehen, Kompetenz und Erfolg, sowie der Interaktion zwischen diesen Variablen und der Qualität der therapeutischen Allianz bei Patienten (n?=?95), die individuelle Drogenberatung im Rahmen der gemeinsamen Drogenabhängigkeits-Behandlungs-Studie des Nationalen Instituts zur Kokain-Abhängigkeit erhielten. Die Ergebnisse unterstützten die vorhergesagte kurvilineare Beziehung zwischen vorgabegetreuem Vorgehen und dem Ergebnis, sowie einer Interaktion dieses kurvilinearen Effekts und der Allianz zu einem frühen Zeitpunkt der Behandlung. Für Patienten mit einer starken therapeutischen Allianz war das vorgabengetreue Vorgehen des Beraters zum Behandlungsmodell für das Behandlungsergebnis ohne Einfluss. Dagegen zeigte ein moderat vorgabengetreues Vorgehen des Beraters (im Vergleich zu einem hohen oder niedrigen Festhalten an den Vorgaben) den besten Erfolg, wenn die Allianz schwächer war. Die vorliegenden Ergebnisse legen nahe, dass Studien zur Beziehung zwischen einem Vorgehen des Therapeuten konform zu den Behandlungsrichtlinien und dem Ergebnis den komplexen Moderatoreffekt der therapeutischen Allianz berücksichtigen müssen.

Cette étude a testé des hypothèses au sujet de relations linéaires et curvilinéaires entre adhérence, compétence et résultat, et des interactions de ces effets avec la qualité de l'alliance thérapeutique chez des patients (N?=?95) qui avaient reçu du counseling individuel pour abus de drogues dans le cadre de l'Etude en Collaboration de l'Institut National pour l'Abus de Drogues sur le Traitement de la Cocaïne. Les résultats apportent du soutien à l'hypothèse d'une relation curvilinéaire entre adhérence et résultat ainsi que d'une interaction entre cet effet curvilinéaire et l'alliance en phase précoce du traitement. Pour les patients avec une alliance thérapeutique forte, l'adhérence du conseiller au modèle de traitement ne jouait pas de rôle essentiel pour le résultat du traitement. En cas d'alliance plus faible, par contre, un niveau modéré (versus haut ou bas) d'adhérence du conseiller était associé avec le meilleur résultat. Ces résultats suggèrent que des études de la relation entre l'adhérence du thérapeute à un modèle de traitement et le résultat devraient tenir compte l'effet de modération complexe de l'alliance thérapeutique.

Este estudio testeó hipótesis vinculadas con las relaciones lineales y curvilíneas entre adherencia, competencia y resultado así también como interacciones de estos efectos con la calidad de la alianza terapéutica entre pacientes (n?=?95) que recibieron Cunseling individual por drogas como parte del Estudio Colaborativo del tratamiento por cocaína del Instituto Nacional para el Abuso de Drogas. Los resultados apoyaron la hipótesis de la relación curvilineal entre adherencia y resultado, así también como la interacción entre este efecto curvilineal y la alianza temprana. Para los pacientes con una fuerte alianza terapéutica, la adherencia del consejero al modelo de tratamiento fue totalmente irrelevante al resultado. En los casos en los que la alianza fue más débil, en cambio, un nivel de adherencia del consejero (ni alta ni baja) estuvo asociada con el resultado mejor. Estos resultados sugieren que los estudios de la relación entre la adherencia del terapeuta a los modelos de tratamiento y resultado han de tener en cuenta el efecto moderador de la alianza terapéutica.

Let me know pls if this is all. Best, Beatriz

Il ruolo dell'adesione e della competenza del terapeuta ed il ruolo dell'alleanza nella previsione dell'esito del counseling individuale per le droghe: i risultati dall'Istituto Nazionale sull'abuso di droghe in equipe con lo Studio di trattamento della cocaina. Questo studio ha valutato le ipotesi collegate alle relazioni lineari e curvilinee tra adesione, competenza ed esito e le interazioni tra questi effetti con la qualità dell'alleanza terapeutica in pazienti (N: 95) che hanno ricevuto un counseling individuale sulle droghe come parte dello Studio di trattamento della cocaina in collaborazione con l'Istituto Nazionale di abuso di droghe.

I risultati supportano un'ipotizzata relazione curvilinea tra adesione ed esito, così come un'interazione tra questo effetto curvilineo e l'alleanza all'inizio del trattamento.

Per i pazienti con una forte alleanza terapeutica, l'adesione del counselor al modello di trattamento è stata essenzialmente irrilevante rispetto all'esito del trattamento. Quando l'alleanza era pi[ugrave] debole, al contrario, un moderato (verso l'alto o il basso) livello di adesione del counselor è stato associato con un miglior esito.

I risultati attuali suggeriscono che gli studi sulla relazione tra l'adesione del terapeuta ai modelli di trattamento e l'esito potrebbero aver bisogno di considerare il complesso effetto moderatore dell'alleanza terapeutica.

Este estudo estudou as hipóteses de relação linear e curvilínea entre adesão, competência e resultado e as interacç[otilde]es destes efeitos com a qualidade da aliança terapêutica em pacientes (N=95) que receberam aconselhamento individual para toxicodependência como parte do Estudo Colaborativo do Tratamento da Dependência da Cocaína do Instituto Nacional para o Abuso de Drogas. Os resultados apoiaram a relação curvilínea entre adesão e resultado, bem como uma interacção entre este efeito curvilíneo e aliança inicial. Para pacientes com uma forte aliança terapêutica, a adesão do terapeuta ao modelo terapêutico era, essencialmente, irrelevante para os resultados do tratamento. Quando a aliança era mais fraca, em contrate, um nível moderado (vs. baixo ou elevado) de adesão do terapeuta estava associado a melhores resultados. Estes resultados sugerem que estudos da relação entre adesão do terapeuta a modelos de tratamento e resultados terapêuticos podem necessitar de ter em consideração o efeito moderador complexo da aliança terapêutica.

     

Immunichemical determination of cathodal elastase in human duodenal juice.

In human duodenal juice enzymes hydrolysing the elastase substrate succinyl-trialanine-p-nitroanilide have both an anodal and cathodal mobility in agarose gel electrophoresis. The cathodal enzyme, also having an elastinolytic activity, was purified. An application of electroimmunoassay for separate determination of this cathodal elastase is presented. Parallel estimations of esterolytic, elastinolytic and immunochemical activities in duodenal juice from a group of children revealed discrepancies suggesting both variations in the distribution of the two forms of "elastases", and presence of inactive forms.