Gene expression changes following extinction testing in a heroin behavioral incubation model

<p>Abstract</p> <p>Background</p> <p>A number of gene expression studies have investigated changes induced by drug exposure, but few reports describe changes that persist following relapse. In this study, genome-wide analysis of gene expression was conducted following an extinction session (90 min) in rats that expressed behavioral incubation of heroin-seeking and goal-directed behavior. As an important modulator of goal-directed behavior, the medial prefrontal cortex (mPFC) was the target of genomic analysis. Rats were trained to self-administer heroin during 3 h daily sessions for 14 d. Following the self-administration period, rats were reintroduced to the self-administration chambers for a 90-minute extinction session in which they could seek heroin, but received none. Extinction sessions were conducted on groups after either 1 d or 14 d of drug-free enforced abstinence to demonstrate behavioral incubation.</p> <p>Results</p> <p>Behavioral data demonstrated incubation (increased expression) of heroin-seeking and goal-directed behavior after the 14 d abstinent period. That is, following 14 d of enforced abstinence, animals displayed heightened drug-seeking behavior when returned to the environment where they had previously received heroin. This increased drug-seeking took place despite the fact that they received no drug during this extinction session. Whole genome gene expression analysis was performed and results were confirmed by quantitative real-time PCR (RT-qPCR). Microarrays identified 66 genes whose expression was identified as changed by at least 1.4 fold (p < 0.02) following 14 d of abstinence and the 90-minute extinction session compared to the saline treated controls. Orthogonal confirmation by RT-qPCR demonstrated significant alterations in <it>bdnf</it>, <it>calb1</it>, <it>dusp5</it>, <it>dusp6</it>, <it>egr1</it>, <it>npy</it>, <it>rgs2</it>.</p> <p>Conclusion</p> <p>Ontological analysis indicates that several of the genes confirmed to be changed are important for neuroplasticity, and through that role may impact learning and behavior. The importance of drug-seeking behavior and memory of previous drug-taking sessions suggest that such genes may be important for relapse. The global gene expression analysis adds to the knowledge of heroin-induced changes and further highlights similarities between heroin and other drugs of abuse.</p

Drugs-related death soon after hospital discharge among drug treatment clients in Scotland:record linkage, validation and investigation of risk factors.

We validate that the 28 days after hospital-discharge are high-risk for drugs-related death (DRD) among drug users in Scotland and investigate key risk-factors for DRDs soon after hospital-discharge. Using data from an anonymous linkage of hospitalisation and death records to the Scottish Drugs Misuse Database (SDMD), including over 98,000 individuals registered for drug treatment during 1 April 1996 to 31 March 2010 with 705,538 person-years, 173,107 hospital-stays, and 2,523 DRDs. Time-at-risk of DRD was categorised as: during hospitalization, within 28 days, 29-90 days, 91 days-1 year, >1 year since most recent hospital discharge versus 'never admitted'. Factors of interest were: having ever injected, misuse of alcohol, length of hospital-stay (0-1 versus 2+ days), and main discharge-diagnosis. We confirm SDMD clients' high DRD-rate soon after hospital-discharge in 2006-2010. DRD-rate in the 28 days after hospital-discharge did not vary by length of hospital-stay but was significantly higher for clients who had ever-injected versus otherwise. Three leading discharge-diagnoses accounted for only 150/290 DRDs in the 28 days after hospital-discharge, but ever-injectors for 222/290. Hospital-discharge remains a period of increased DRD-vulnerability in 2006-2010, as in 1996-2006, especially for those with a history of injecting

Insights into the voltage-gated sodium channel, NaV1.8, and its role in visceral pain perception

Pain is a major issue in healthcare throughout the world. It remains one of the major clinical issues of our time because it is a common sequela of numerous conditions, has a tremendous impact on individual quality of life, and is one of the top drivers of cost in medicine, due to its influence on healthcare expenditures and lost productivity in those affected by it. Patients and healthcare providers remain desperate to find new, safer and more effective analgesics. Growing evidence indicates that the voltage-gated sodium channel Nav1.8 plays a critical role in transmission of pain-related signals throughout the body. For that reason, this channel appears to have strong potential to help develop novel, more selective, safer, and efficacious analgesics. However, many questions related to the physiology, function, and clinical utility of Nav1.8 remain to be answered. In this article, we discuss the latest studies evaluating the role of Nav1.8 in pain, with a particular focus on visceral pain, as well as the steps taken thus far to evaluate its potential as an analgesic target. We also review the limitations of currently available studies related to this topic, and describe the next scientific steps that have already been undertaken, or that will need to be pursued, to fully unlock the capabilities of this potential therapeutic target

Homozygosity for the SCN10A Polymorphism rs6795970 Is Associated With Hypoalgesic Inflammatory Bowel Disease Phenotype

Background: Hypoalgesic inflammatory bowel disease (IBD), a condition in which patients with active disease do not perceive and/or report abdominal pain, is associated with serious complications and there is a lack of cost-effective, reliable diagnostic methods to identify “at-risk” patients. The voltage-gated sodium channels (VGSC's), Nav1.7, Nav1.8, and Nav1.9, are preferentially expressed on nociceptive neurons, and have been implicated in visceral inflammatory pain. At least 29 VGSC single nucleotide polymorphisms (SNPs) have been implicated in chronic somatic pain syndromes, but little is known about their role in human visceral sensation. We hypothesized that disruptive VGSC polymorphisms result in anti-nociceptive behavior in IBD.Methods and Findings: We performed targeted exome sequencing and/or TaqMan genotyping to evaluate the Nav1.7, Nav1.8, and Nav1.9 genes (SCN9A, SCN10A and SCN11A) in 121 IBD patients (including 41 “hypoalgesic” IBD patients) and 86 healthy controls. Allelic and genotypic frequencies of polymorphisms were compared among study groups who had undergone characterization of intestinal inflammatory status and abdominal pain experience. Forty-nine total exonic SNPs were identified. The allelic frequency of only one non-synonymous SNP (rs6795970 [SCN10A]) approached significance in hypoalgesic IBD patients when compared to other IBD patients (p = 0.096, Fisher's exact test). Hypoalgesic IBD patients were more likely to be homozygous for this polymorphism (46 vs. 22%, p = 0.01, Fisher's exact test).Conclusions: This is the first human study to demonstrate a link between a genetic variant of SCN10A and abdominal pain perception in IBD. These findings provide key insights into visceral nociceptive physiology and new diagnostic and therapeutic targets to consider in IBD and other gastrointestinal conditions associated with chronic abdominal pain. Further studies are required to elucidate the precise pathophysiological impact of the rs6795970 polymorphism on human gastrointestinal nociception

Context and culture associated with alcohol use amongst youth in major urban cities: A cross-country population based survey

Background: Alcohol consumption patterns are dependent upon culture and context. The aim of this study was to interview people aged 18–34 year old living in four cities in different regions of the world to explore differences in a range of alcohol measures to assist in determining culturally appropriate alcohol initiatives for this age group. Method: Multistage random sampling was consistent across the four cities (Ilorin (Nigeria), Wuhan (China), Montevideo (Uruguay) and Moscow (Russia)). The questionnaire was forward and back translated into relevant languages and face-to-face interviewing undertaken. The data were weighted to the population of each city. Uni-variable analysis (ever consumed, first time consumed, age when drunk for first time, number of days consumed, type consumed) and logistic regression modeling were undertaken. The final model for each city was adjusted for age, sex, marital status, highest education and employment status. In total 6235 interviews were undertaken (1391 in Ilorin, 1600 in Montevideo, 1604 in Moscow and 1640 in Wuhan). Results: Alcohol was consumed by 96.4% in Montevideo, 86.1% in Moscow, 53.4% in Wuhan and 33.3% in Ilorin. There was very little difference by gender except Ilorin males were more likely to consume alcohol than females. Alcohol was consumed on more days for Ilorin males; Wuhan females consumed alcohol on the least number of days; Ilorin had the most abstainers; Montevideo and Moscow the highest proportion of light drinkers; Ilorin and Montevideo the highest proportion of heavy drinkers. Differences by type of alcohol were also apparent. The final logistic regression model provided different models including higher alcohol consumption rates for males, 25–34 years of age, divorced/separated marital status and employed part time for Ilorin respondents; males and higher educated for Montevideo; males, 25 to 29 years of age and higher educated for Moscow; and 25–29 years of age, non-married and vocationally trained for those in Wuhan. Conclusion: Alcohol consumption in these four cities does not increase with age as found in most high income countries. The alcohol consumption patterns during this stage of the life cycle are important to assess so that high level, as well as country-specific, planning and interventions can be implemented

Barriers to disseminating brief CBT for voices from a lived experience and clinician perspective

Access to psychological therapies continues to be poor for people experiencing psychosis. To address this problem, researchers are developing brief interventions that address the specific symptoms associated with psychosis, i.e., hearing voices. As part of the development work for a brief Cognitive Behaviour Therapy (CBT) intervention for voices we collected qualitative data from people who hear voices (study 1) and clinicians (study 2) on the potential barriers and facilitators to implementation and engagement. Thematic analysis of the responses from both groups revealed a number of anticipated barriers to implementation and engagement. Both groups believed the presenting problem (voices and psychosis symptoms) may impede engagement. Furthermore clinicians identified a lack of resources to be a barrier to implementation. The only facilitator to engagement was reported by people who hear voices who believed a compassionate, experienced and trustworthy therapist would promote engagement. The results are discussed in relation to how these barriers could be addressed in the context of a brief intervention using CBT techniques

A qualitative study of service provision for alcohol related health issues in mid to later life

AIMS:Epidemiological surveys over the last 20 years show a steady increase in the amount of alcohol consumed by older age groups. Physiological changes and an increased likelihood of health problems and medication use make older people more likely than younger age groups to suffer negative consequences of alcohol consumption, often at lower levels. However, health services targeting excessive drinking tend to be aimed at younger age groups. The aim of this study was to gain an in-depth understanding of experiences of, and attitudes towards, support for alcohol related health issues in people aged 50 and over. METHODS:Qualitative interviews (n = 24, 12 male/12 female, ages 51-90 years) and focus groups (n = 27, 6 male/21 female, ages 50-95 years) were carried out with a purposive sample of participants who consumed alcohol or had been dependent. FINDINGS:Participants' alcohol misuse was often covert, isolated and carefully regulated. Participants tended to look first to their General Practitioner for help with alcohol. Detoxification courses had been found effective for dependent participants but only in the short term; rehabilitation facilities were appreciated but seen as difficult to access. Activities, informal groups and drop-in centres were endorsed. It was seen as difficult to secure treatment for alcohol and mental health problems together. Barriers to seeking help included functioning at a high level, concern about losing positive aspects of drinking, perceived stigma, service orientation to younger people, and fatalistic attitudes to help-seeking. Facilitators included concern about risk of fatal illness or pressure from significant people. CONCLUSION:Primary care professionals need training on improving the detection and treatment of alcohol problems among older people. There is also a compelling need to ensure that aftercare is in place to prevent relapse. Strong preferences were expressed for support to be provided by those who had experienced alcohol problems themselves

Rescuing Suboptimal Patient-Reported Outcome Instrument Data in Clinical Trials: A New Strategy

Background: Psychometric instruments such as the Repeated Battery for the Assessment of Neuropsychological Status (RBANS) are commonly used under conditions for which they were not developed or validated. They may then generate troublesome data that could conceal potential findings. Methods: Based on a previously published refinement of the RBANS, we reanalyzed the data on 303 patients from two National Institutes of Health (NIH) trails in Parkinson’s disease and contrasted the results using the original versus refined scores. Results: Findings from the original RBANS scores were inconsistent; however, use of the refined scores produced potential findings that were in agreement with independent reports. Conclusion: This study demonstrates that, for negative trials using instrument scores as primary outcomes, it is possible to rescue potential findings. The key to this new strategy is to validate and refine the instrument for the specific disease and conditions under study and then to reanalyze the data. This study offers a demonstration of this new strategy for general approaches