Differential COMT expression and behavioral effects of COMT inhibition in male and female Wistar and alcohol preferring rats

Polymorphisms of the catechol-O-methyl transferase (COMT) gene have been associated with alcoholism, suggesting that alterations in the metabolism of catecholamines may be a critical component of the neuropathology of alcoholism. In the current experiments, the COMT inhibitor tolcapone was utilized in an operant behavioral model of reinforcer-seeking and drinking to determine if this compound was capable of remediating the excessive seeking and drinking phenotype of the alcohol-preferring P rat. Tolcapone was administered to male and female alcohol-reinforced P and Wistar rats. Additionally, tolcapone was administered to male sucrose-reinforced P and Wistar rats to determine if its effects also extended to a natural reinforcer. Animals were trained to make an operant response that resulted in 20 min uninterrupted access to the reinforcer solutions. Tolcapone had no effect in female rats on either seeking or consumption of ethanol. However, reductions of both reinforcer seeking and consumption were observed in male P rats, but only of seeking in Wistars. In separate experiments, using reinforcer naïve male and female animals, COMT expression was assessed via Western Blot analysis. Sex differences in COMT expression were also observed, where male P rats exhibited a marked reduction in protein expression relative to females in the PFC. Sex differences were not observed for Wistars or in the striatum and hippocampus. These data complement our previous findings in which tolcapone reduced cue-evoked responses in P rats and further suggest clinical utility of COMT inhibitors in the treatment of addiction disorders, specifically in male high drinkers

Systematic review of measurement properties of questionnaires measuring somatization in primary care patients

Objective The aim of this review is to critically appraise the evidence on measurement properties of self-report questionnaires measuring somatization in adult primary care patients and to provide recommendations about which questionnaires are most useful for this purpose. Methods We assessed the methodological quality of included studies using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. To draw overall conclusions about the quality of the questionnaires, we conducted an evidence synthesis using predefined criteria for judging the measurement properties. Results We found 24 articles on 9 questionnaires. Studies on the Patient Health Questionnaire-15 (PHQ-15) and the Four-Dimensional Symptom Questionnaire (4DSQ) somatization subscale prevailed and covered the broadest range of measurement properties. These questionnaires had the best internal consistency, test-retest reliability, structural validity, and construct validity. The PHQ-15 also had good criterion validity, whereas the 4DSQ somatization subscale was validated in several languages. The Bodily Distress Syndrome (BDS) checklist had good internal consistency and structural validity. Some evidence was found for good construct validity and criterion validity of the Physical Symptom Checklist (PSC-51) and good construct validity of the Symptom Check-List (SCL-90-R) somatization subscale. However, these three questionnaires were only studied in a small number of primary care studies. Conclusion Based on our findings, we recommend the use of either the PHQ-15 or 4DSQ somatization subscale for somatization in primary care. Other questionnaires, such as the BDS checklist, PSC-51 and the SCL-90-R somatization subscale show promising results but have not been studied extensively in primary care. © 2017 Elsevier Inc

Excessive Ethanol-Seeking as Related to Impulsive Behavior as Measured by Delay Discounting

poster abstractThe discounting of delayed rewards, a specific type of impulsive behavior, has been associated with alcohol use disorders. However, the way in which this characteristic is related to the genetic and behavioral paths which lead to high-drinking is a newly emerging area of alcohol research. Rodents selectively bred for extreme high vs. low alcohol preference have shown parallel patterns of delay discounting. This study investigated whether or not delayed discounting is preferentially related to ethanol-seeking vs. consumption. Alcohol preferring rats (P; n=5), High Alcohol Drinking rats (HAD2; n=15), and Long Evans rats (LE; n=11) were used and have previously been identified as high seeking/high drinking, moderate seeking/high drinking, and moderate seeking/moderate drinking, respectively. Six levels of delay (0, 2, 4, 8, 12 and 16 seconds) were assessed using a sucrose reinforcer. The average indifference points for each delay were then fitted to hyperbolic equations to yield a single parameter (k). An ANOVA for those values, along with post hoc testing, revealed Ps to have larger k values than both HAD2s and LEs. However, the HAD2s and LEs were not different from each other. A mixed ANOVA for indifference points showed a main effect of Delay (p<.01), Group (p<.01), and no group/delay interaction (p=.08). The main effect of group revealed the same pattern of findings for the indifference points as for the k values. Both the higher k values and the lower indifference points of the Ps indicate their steeper discounting in comparison to both HAD2s and LE. These results suggest that this measure of impulsivity could be associated with the quantity of ethanol-seeking, and not just with the inclination to consume ethanol. These results extend previous findings, and as all animals were ethanol naïve, these results support the idea that increased impulsivity is a characteristic that precedes addictive disorders

What research agenda could be generated from the European General Practice Research Network concept of Multimorbidity in Family Practice?

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: Multimorbidity is an intuitively appealing, yet challenging, concept for Family Medicine (FM). An EGPRN working group has published a comprehensive definition of the concept based on a systematic review of the literature which is closely linked to patient complexity and to the biopsychosocial model. This concept was identified by European Family Physicians (FPs) throughout Europe using 13 qualitative surveys. To further our understanding of the issues around multimorbidity, we needed to do innovative research to clarify this concept. The research question for this survey was: what research agenda could be generated for Family Medicine from the EGPRN concept of Multimorbidity? METHODS: Nominal group design with a purposive panel of experts in the field of multimorbidity. The nominal group worked through four phases: ideas generation phase, ideas recording phase, evaluation and analysis phase and a prioritization phase. RESULTS: Fifteen international experts participated. A research agenda was established, featuring 6 topics and 11 themes with their corresponding study designs. The highest priorities were given to the following topics: measuring multimorbidity and the impact of multimorbidity. In addition the experts stressed that the concept should be simplified. This would be best achieved by working in reverse: starting with the outcomes and working back to find the useful variables within the concept. CONCLUSION: The highest priority for future research on multimorbidity should be given to measuring multimorbidity and to simplifying the EGPRN model, using a pragmatic approach to determine the useful variables within the concept from its outcomes.The study had a Grant of 8000 Euros from the EGPRN

Which DSM validated tools for diagnosing depression are usable in primary care research? A systematic literature review

IntroductionDepression occurs frequently in primary care. Its broad clinical variability makes it difficult to diagnose. This makes it essential that family practitioner (FP) researchers have validated tools to minimize bias in studies of everyday practice. Which tools validated against psychiatric examination, according to the major depression criteria of DSM-IV or 5, can be used for research purposes

Effects of Ethanol and NAP on Cerebellar Expression of the Neural Cell Adhesion Molecule L1

The neural cell adhesion molecule L1 is critical for brain development and plays a role in learning and memory in the adult. Ethanol inhibits L1-mediated cell adhesion and neurite outgrowth in cerebellar granule neurons (CGNs), and these actions might underlie the cerebellar dysmorphology of fetal alcohol spectrum disorders. The peptide NAP potently blocks ethanol inhibition of L1 adhesion and prevents ethanol teratogenesis. We used quantitative RT-PCR and Western blotting of extracts of cerebellar slices, CGNs, and astrocytes from postnatal day 7 (PD7) rats to investigate whether ethanol and NAP act in part by regulating the expression of L1. Treatment of cerebellar slices with 20 mM ethanol, 10−12 M NAP, or both for 4 hours, 24 hours, and 10 days did not significantly affect L1 mRNA and protein levels. Similar treatment for 4 or 24 hours did not regulate L1 expression in primary cultures of CGNs and astrocytes, the predominant cerebellar cell types. Because ethanol also damages the adult cerebellum, we studied the effects of chronic ethanol exposure in adult rats. One year of binge drinking did not alter L1 gene and protein expression in extracts from whole cerebellum. Thus, ethanol does not alter L1 expression in the developing or adult cerebellum; more likely, ethanol disrupts L1 function by modifying its conformation and signaling. Likewise, NAP antagonizes the actions of ethanol without altering L1 expression

Cross-Cultural Validation of the Definition of Multimorbidity in the Bulgarian Language.

INTRODUCTION: Multimorbidity is a health issue with growing importance. During the last few decades the populations of most countries in the world have been ageing rapidly. Bulgaria is affected by the issue because of the high prevalence of ageing population in the country with multiple chronic conditions. The AIM of the present study was to validate the translated definition of multimorbidity from English into the Bulgarian language. MATERIALS AND METHODS: The present study is part of an international project involving 8 national groups. We performed a forward and backward translation of the original English definition of multimorbidity using a Delphi consensus procedure. RESULTS: The physicians involved accepted the definition with a high percentage of agreement in the first round. The backward translation was accepted by the scientific committee using the Nominal group technique. DISCUSSION: Some of the GPs provided comments on the linguistic expressions which arose in order to improve understanding in Bulgarian. The remarks were not relevant to the content. The conclusion of the discussion, using a meta-ethnographic approach, was that the differences were acceptable and no further changes were required. CONCLUSIONS: A native version of the published English multimorbidity definition has been finalized. This definition is a prerequisite for better management of multimorbidity by clinicians, researchers and policy makers

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. Objective The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. Results The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Conclusions Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression