The University of Rhode Island Change Assessment Scale (URICA) is a widely used measure of readiness to change. To evaluate the URICA's ability to discriminate among alcohol abusers with and without co-occurring major depression, the authors administered it to 193 outpatients court-referred for alcohol treatment. Estimates of internal consistency suggest that scoring the URICA using its traditional factors, as well as using the newer Readiness to Change index, produced variable yet adequately reliable scores. Further, the URICA detected statistically significant differences in motivation to change an alcohol problem between an alcohol use disorder group (AD; n = 131) and an alcohol use disorder with co-occurring depression group (AD/D; n = 62) with the AD/D group showing greater readiness to change. For the AD/D group, separate URICAs were given for alcohol use and depressed mood. Confirming previous findings, results suggest the URICA may lack sensitivity to discriminate among two simultaneously occurring psychological disorders.

Neuropeptides are special in their expression profiles restricted to neuronal subpopulations and low tissue mRNA levels. Genetic, epigenetic and transcriptional mechanisms that define spatiotemporal expression of the neuropeptide genes have utmost importance for the formation and functions of neural circuits in normal and pathological human brain. This thesis focuses on regulation of transcription of the opioid/nociceptin genes, the largest neuropeptide family, and on identification of adaptive changes in these mechanisms associated with alcoholism as model human pathology. Two epigenetic mechanisms, the common for most cells in the dorsolateral prefrontal cortex (dlPFC) and the neuron-subpopulation specific that may orchestrate prodynorphin (PDYN) transcription in the human dlPFC have been uncovered. The first, repressive mechanism may operate through control of DNA methylation/demethylation in a short, nucleosome size promoter CpG island (CGI). The second mechanism may involve USF2, the sequence–specific methylation–sensitive transcription factor which interaction with its target element in the CpG island results in USF2 and PDYN co-expression in the same neurons. The short PDYN promoter CGI may function as a chromatin element that integrates cellular and environmental signals through changes in methylation and transcription factor binding. Alterations in USF2–dependent PDYN transcription are affected by the promoter SNP (rs1997794: T>C) under transition to pathological state, i.e. in the alcoholic brain. This and two other PDYN SNPs that are most significantly associated with alcoholism represent CpG-SNPs, which are differentially methylated in the human dlPFC. The T, low risk allele of the promoter SNP forms a noncanonical AP-1–binding element. JUND and FOSB proteins, which may form homo- or heterodimers have been identified as dominant constituents of AP-1 complex. The C, non-risk variant of the PDYN 3′ UTR SNP (rs2235749 SNP: C>T) demonstrated significantly higher methylation in alcoholics compared to controls. PDYN mRNA and dynorphin levels significantly and positively correlated with methylation of the PDYN 3′ UTR CpG-SNP suggesting its involvement in PDYN regulation. A DNA–binding factor with differential binding affinity for the T allele and methylated and unmethylated C alleles of the PDYN 3′ UTR SNP (the T allele specific binding factor, Ta-BF) has been discovered, which may function as a regulator of PDYN transcription. These findings emphasize the complexity of PDYN regulation that determines its expression in specific neuronal subpopulations and suggest previously unknown integration of epigenetic, transcriptional and genetic mechanisms that orchestrate alcohol–induced molecular adaptations in the human brain. Given the important role of PDYN in addictive behavior, the findings provide a new insight into fundamental molecular mechanisms of human brain disorder. In addition to PDYN in the dlPFC, the PNOC gene in the hippocampus and OPRL1 gene in central amygdala that were downregulated in alcoholics may contribute to impairment of cognitive control over alcohol seeking and taking behaviour.

A growing body of research is examining effective treatment(s) for individuals with comorbid posttraumatic stress disorder (PTSD) and alcohol dependence (AD). However, treatments for this comorbid population have been inadequately studied in the longer term. This study represents a long-term follow-up assessment of a randomized controlled trial that compared combined therapy (prolonged exposure + naltrexone) with monotherapies (prolonged exposure or naltrexone) for patients with PTSD and AD (see Foa, Yusko, McLean et al., 2013). Attempts were made to contact 120 participants 5-10 years after the original trial to assess the maintenance of treatment gains. Nineteen individuals were located and agreed to participate. A series of mixed ANCOVAs were conducted with PTSD symptom severity and percentage of days drinking and heavy drinking as the dependent variables. Findings revealed that reductions in PTSD symptoms and drinking behaviors generally were maintained 5-10 years after treatment. There was some relapse in heavy drinking days, and combination treatment was most effective for long-term PTSD outcomes. Challenges of conducting follow-up research with this population, implications and limitations of the present findings, and directions for future research are discussed.

Highly organised and differentiated neural circuits form and unite to link the cortex with the basal ganglia and thalamus to mediate movement, cognition and behaviour. Previous assertions that the basal ganglia primarily acted to filter cortical information to facilitate motor outputs only have since given way to an understanding of the basal ganglia as a relay and gating structure with functionally and structurally segregated inputs, functions and outputs. Thus, cortical – basal ganglia circuits can be segregated into three broadly separable functional domains mediating motor (primary and supplementary motor cortex (SMA) and putamen), cognitive (dorsolateral prefrontal cortex (dlPFC) and caudate), and limbic (ventromedial prefrontal cortex and ventral striatum (VS)) processes. In addition, cognitive and behavioural programs that pass through the cortical – basal ganglia circuitry can be subject to filtering by the subthalamic nucleus (STN), which receives direct projections from the cortex. This work first demonstrated the functional organisation of segregated intrinsic cortical – basal ganglia circuits in humans, alongside a detailed map of functional subzones within STN, a small and technically inaccessible midbrain structure. The behavioural relevance of the defined cortical – basal ganglia circuits was investigated by examining the cognitive constructs of impulsivity and compulsivity. Waiting impulsivity, a tendency towards rapid premature responses that has been associated with compulsive drug use, was associated with connectivity between limbic regions including subgenual anterior cingulate cortex, VS and STN. However, motor impulsivity, in the form of stopping ability, was associated with motoric regions including pre-SMA and STN. Compulsivity was captured as deficits in: reversal learning, implicating lateral orbitofrontal cortex; attentional shifting, implicating dlPFC; and habit learning, implicating SMA. Neural circuit changes were also examined in individuals with alcohol dependence and binge drinkers. Waiting impulsivity was elevated in both groups and the functional connectivity, microstructural integrity and anatomical connectivity of the neural circuit underlying waiting impulsivity were associated with problematic drinking behaviours in both groups. Together, this work establishes that discrete functional subzones of small subcortical regions can be differentiated in humans and that their behavioural correlates can be similarly mapped. The definition of intrinsic network architecture underlying a particular behaviour and the demonstration its disturbance in psychiatric groups will crucially inform the development of future diagnostic and therapeutic models.

Submitted by Irene Nascimento (irene.kessia@ufpe.br) on 2016-06-29T17:19:51Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TEMPERAMENTO.pdf: 515563 bytes, checksum: f0effde4fd02a7e920fe7e33fd43137f (MD5) / Made available in DSpace on 2016-06-29T17:19:51Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) TEMPERAMENTO.pdf: 515563 bytes, checksum: f0effde4fd02a7e920fe7e33fd43137f (MD5) Previous issue date: 2015-03-06 / O temperamento é um traço herdado geneticamente, e constitui a base do humor, do comportamento e da personalidade. Acredita-se atualmente que o temperamento esteja intimamente relacionado ao desenvolvimento dos transtornos mentais. O alcoolismo é um transtorno mental grave, que se transformou num sério problema de saúde pública mundial, e o seu tratamento ainda é muito deficiente, dificultando muito a recuperação total destes pacientes. A adoção urgente de novas estratégias terapêuticas é necessária para que esta dependência seja controlada de forma mais eficaz. Alguns estudos tem mostrado associação entre traços característicos de temperamento e a dependência por álcool, e esta possível relação pode ser uma ferramenta importante como medida preventiva e para o aperfeiçoamento no processo terapêutico destes indivíduos. Objetivo: Verificar a associação entre temperamentos emocional e afetivo e a dependência por álcool. Método: Trata-se de um estudo transversal, com amostragem não probabilística do tipo intencional, realizado em 50 indivíduos dependentes de álcool, tratados no Núcleo Especializado em Dependência Química do Hospital das Clínicas da Universidade Federal de Pernambuco (NEDEQ/HC/UFPE) – do município do Recife, e no Centro de Atenção Psicossocial – Álcool e Drogas – do município do Cabo de Santo Agostinho-PE (CAPS-AD). Inicialmente, o estudo caracterizou o perfil sócio-demográfico dos sujeitos e, em seguida, selecionou os dependentes de álcool por meio do instrumento The Alcohol Use Identification Test (AUDIT), e identificou os tipos de temperamento emocional e afetivo através da escala The Affective and Emotional Composite Temperament Scale (AFECTS). Resultados: A amostra foi composta na sua maioria por indivíduos do sexo masculino, com média de idade de 44 anos. A pontuação média obtida no AUDIT foi de 30,08. Quanto ao AFECTS, a seção emocional mostrou maior prevalência nos altos níveis de vontade e nos baixos níveis de sensibilidade e inibição, enquanto que na seção afetiva, houve uma predominância no subgrupo dos temperamentos instáveis, com uma maior prevalência do temperamento ciclotímico em toda a amostra. Nos ciclotímicos, realmente foi encontrado altos níveis de desejo, raiva e sensibilidade, e de baixos níveis de coping. Conclusão: Houve associação entre temperamento e dependência por álcool na amostra. Os dados deste e de outros estudos sobre temperamento podem auxiliar na prevenção, no diagnóstico e no tratamento de indivíduos com dependência por álcool. É necessário que mais estudos esclareçam esta relação e ajudem a aperfeiçoar os modelos de tratamento do alcoolismo. / The temperament is a genetically inherited trait, and forms the basis of mood, behavior and personality. It is currently believed that temperament is closely related to the development of mental disorders. Alcoholism is a serious mental disorder, which has become a serious public health problem worldwide, and its treatment is still very poor, making it difficult to complete recovery of these patients. The urgent adoption of new therapeutic strategies is necessary so that this dependence is controlled more effectively. Some studies have shown an association between temperament traits and alcohol dependence, and this possible relationship can be an important tool as a preventive measure and to improve the therapeutic process these individuals. Objective: To investigate the association between emotional and affective temperaments and alcohol dependence. Method: This was a cross-sectional study with non-probabilistic intentional sampling, conducted in 50 alcohol-dependent individuals treated at the Center for Chemical Dependency Specialist, Hospital das Clinicas, Federal University of Pernambuco (NEDEQ / HC / UFPE) - the city of Recife, and Psychosocial Care Center - Alcohol and Drugs - the city of Cabo de Santo Agostinho- PE (CAPS-AD). Initially, the study characterized the socio-demographic profile of the subjects and then selected alcoholics by means of the instrument The Alcohol Use Disorder Identification Test (AUDIT), and identified the types of emotional and affective temperament scale through The Affective and Emotional Composite Temperament Scale (AFECTS). Results: The sample consisted mostly of males, with a mean age of 44 years. The average score on the AUDIT was 30.08. Regarding AFECTS, emotional section showed higher prevalence in high levels of volition and the low levels of sensitivity and inhibition, whereas there was a predominance in the subgroup of unstable affective temperaments in section, with a higher prevalence of cyclothymic temperament in the whole sample. In cyclothymic, was actually found high levels of desire, anger and sensibility, and low levels of coping. Conclusion: There was an association between temperament and alcohol dependence in the sample. The data from this and other studies temper may assist in the prevention, diagnosis and treatment of patients with alcohol dependence. It is necessary that further studies clarify this relationship and help improve treatment models of alcoholism.

Le nalméfène représente une option nouvelle dans le traitement de l’alcoolodépendance. Cette molécule a reçu une AMM européenne en 2013 pour réduire la consommation d’alcool des patients adultes ayant une consommation à risque élevé selon la classification de l’OMS (i.e. plus de 60 g d'alcool par jour pour les hommes, ou plus de 40 g par jour pour les femmes). Toutefois, les avis dans la littérature divergent quant à son intérêt. Nous avons donc souhaité réévaluer le rapport bénéfice-risque de cette molécule en appliquant des méthodes appartenant au domaine de la méta-recherche. Une première méta-analyse des essais randomisés contrôlés comparant le nalméfène par voie orale à un placebo nous a permis de mettre en évidence des tailles d’effet faibles sur les critères de consommation, avec un possible biais d’attrition dans les études. Dans une seconde méta-analyse en réseau évaluant l’efficacité, dans l’indication de réduction des consommations, du nalméfène à d’autres traitements également utilisés dans la prise en charge de l’alcoolodépendance, nous avons conclu à l’absence de preuve de haut niveau de l’efficacité des traitements pharmacologiques pour contrôler la consommation d'alcool chez les patients non abstinents souffrant de troubles liés à l’usage. Enfin, nous avons montré, à travers la réalisation d’un grand nombre de méta analyses, que les choix méthodologiques faits dans les essais randomisés contrôlés évaluant le nalméfène et la naltrexone dans la prise en charge de l’addiction à l’alcool entraînaient une variation substantielle de l’estimation de l’efficacité de ces deux traitements, phénomène également appelé « vibration de l’effet » des traitements. / Nalmefene is a new option in the treatment of alcohol dependence. It was approved by the European Medicines Agency to help reduce alcohol consumption in adults who consume more than 60 g of alcohol per day (for men) or more than 40 g per day (for women). However, researchers’ opinions on the interest of the drug are divided. We therefore planned direct and network meta-analyses to enable an objective reappraisal of the efficacy of nalmefene. A first meta-analysis of randomized controlled trials comparing oral nalmefene with placebo showed small effect sizes on consumption criteria with a possible attrition bias in the studies. In a second network meta-analysis evaluating the comparative efficacy of nalmefene to control drinking with other treatments also used in the management of alcohol dependence, we concluded that there was no high-grade evidence for pharmacological treatment to control drinking in non-abstinent patients with alcohol use disorders. Finally, we explored the vibration of effects in a large number of overlapping indirect meta-analyses comparing nalmefene versus naltrexone to reduce alcohol consumption. We demonstrated that the methodological choices made in randomized controlled trials resulted in a substantial variation in the effect sizes of these two treatments.

Nicotine's rewarding effects are mediated through distinct subunits of nAChRs, encoded by different nicotinic cholinergic receptor (CHRN) genes and expressed in discrete regions in the brain. In the present study, we aimed to test the associations between rare variants at CHRN genes and nicotine dependence (ND), and alcohol dependence (AD). A total of 26,498 subjects with nine different neuropsychiatric disorders in 15 independent cohorts, which were genotyped on Illumina, Affymetrix, or PERLEGEN microarray platforms, were analyzed. Associations between rare variants (minor allele frequency (MAF) <0.05) at CHRN genes and nicotine dependence, and alcohol dependence were tested. The mRNA expression of all Chrn genes in whole mouse brain and 10 specific brain areas was investigated. All CHRN genes except the muscle-type CHRNB1, including eight genomic regions containing 11 neuronal CHRN genes and three genomic regions containing four muscle-type CHRN genes, were significantly associated with ND, and/or AD. All of these genes were expressed in the mouse brain. We conclude that CHRNs are associated with ND (mainly) and AD, supporting the hypothesis that the full catalog of ND/AD risk genes may contain most neuronal nAChRs-encoding genes.

Family, twin, and adoption studies have indicated that genetic and environmental factors contribute to the development of alcohol dependence (AD). We conducted a low-density genome-wide association analysis to identify genetic variants influencing AD. We used 11,120 SNPs from the Affymetrix 10K Genechips genotyped in 116 Caucasian pedigrees (272 nuclear families) from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based association analyses for AD were performed by the PBAT program for autosomal SNPs and by the FBAT program for X-chromosome SNPs. We identified 37 SNPs associated with AD (P < 10 -3), thirteen of which were located in known genes. The most significant association with AD was observed with SNP rs1986644 (P = 8.51 × 10 -6) at 13q22 near EDNRB gene. The next best signal was at 1q41 in USH2A (rs532342, P = 1.07 × 10 -5) and the third region was at 3q25.31 in TIPARP (rs1367311, P = 2.31 × 10 -5). Furthermore, we found support for association of MAOA gene (P = 4.14 × 10 -4 for rs979606). Six of the 37 AD associated SNPs were confirmed to be associated with AD in Australian twin-family study sample (P < 0.05). Interestingly, four SNPs in DSCAML1 at 11q23 reached the genome-wide significance (the top SNP is rs10892169 with P = 5.31 × 10 -9), while rs637547 in NKAIN2 at 6q21 showed strong association with AD (P = 5.11 × 10 -7) in the replication sample. These findings offer the potential for new insights into the pathogenesis of AD and will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in AD.

Indiana University-Purdue University Indianapolis (IUPUI) / Introduction: Externalizing disorders such as attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and oppositional defiant disorder (ODD) have a high prevalence rate in both children of alcoholics and in those with prenatal alcohol exposure (PAE). These disorders are also predictors of alcohol dependence (alcdep), heritable, and share an underlying genetic liability with alcdep. Furthermore, a mother who drinks while pregnant is likely to be alcohol dependent (AD), and vice-versa. This study incorporated these factors into one model, including as well as a measure of broad genetic risk for ADHD and alcdep to test for the contributions of these effects simultaneously. An independent sample was used to confirm the results for PAE and broad genetic risk. The hypothesis is that PAE will increase the risk to ADHD but not to CD or ODD. Methods: Each of these factors was evaluated independently to test if that effect on its own, significantly contributed to each disorder. Another model included several demographic covariates, to determine which of these environmental effects also contributed to the disorder. The final model for each disorder included environmental effects along with the primary effects of interest. Results: PAE resulted in increased risk for the inattentive (INATT) sub-type of ADHD and conduct disorder (CD) in the discovery sample and for the hyperactive-impulsive (HYPIMP), INATT and CD in the replication sample. PAE and the PAE*maternal alcohol dependence interaction increased the risk for ADHD and INATT. A broad genetic risk for ADHD was associated with all disorders except HYPIMP in the replication sample. Conclusion: This study further supports the trending evidence of a unique etiology of ADHD in those with PAE, and more specifically, that INATT and HYPIMP are affected according to two different mechanisms of action, independent of a genetic contribution due to either ADHD or alcohol dependence, both of which also were associated with a risk for INATT. The contribution of PAE to INATT and CD were the only consistent results across all definitions of alcohol exposure and in both datasets, indicating that PAE is a veritable risk for INATT and CD.

No description available.