Alcohol dependence (alcoholism) is a complex disease influenced by both environmental factors and genetic predisposition. Mouse models have been used to study many alcohol dependence-related traits and the genetics that underlie them. Two of the most commonly used mice in alcohol research are the C57BL/6J (B6) and DBA/2J (D2) inbred strains, which diverge on several alcohol-related traits including the development of acute physical dependence. Here we utilized the B6 and D2 mice as a genetic model of acute physical dependence, coupled with mRNA Differential Display (DD) and cDNA microarray analysis, to uncover the transcriptional response of the brain to an acute dose of alcohol as a function of time. About 150 genetically divergent and alcohol-responsive genes were identified between the whole brains of B6 and D2 mice using DD and were added as additional targets to the mouse microarrays. Microarray analysis of the prefrontal cortex of B6 and D2 mice revealed strain-specific, acute alcohol-responsive transcriptome remodeling manifested as temporal patterns of gene expression. Distinct expression patterns were identified for physiologically relevant alcohol-related consequences including intoxication, withdrawal and neuroadaptation. In silico characterization of the differentially expressed genes showed genotype dependent and independent transcriptional regulation and functional classification. In addition, categorization of differentially expressed genes by their cellular profiles revealed that some of the genes were known to be more highly expressed in either excitatory or inhibitory neuronal cell types. Our results indicate that the B6 and D2 prefrontal cortices have very different cellular and molecular responses to acute alcohol exposure. The specific roles that the genes identified in this study may play in mediating the divergent alcohol-related behavior between the strains warrant further study. / text

Objective: Some adolescents and young adults who do not fulfill criteria for DSM-IV alcohol abuse (AA) report symptoms of DSM-IV alcohol dependence (AD) below the diagnostic threshold (diagnostic orphans, DOs; 1 or 2 symptoms). Contemporarily, little is known on the long-term stability, risk of progression to AD, impairment, and drinking patterns possibly associated with this status in the first decades of life. Aim: (1) To identify prevalence rates of the DO status from adolescence to early adulthood. To investigate (2) stability and variability of the DO status over time and (3) associations between DO status, drinking patterns and impairment in comparison to subjects with AA, with AD, or without any symptoms. Method: N = 2039 community subjects (aged 14–24 years at baseline) were assessed at baseline and at about four and ten years after baseline. DSM-IV AUD diagnoses were obtained with the DIA-X/M-CIDI. Results: About 11–12% of the sample was classified as DOs at all waves. Over a period of ten years, 18% of DOs were stable in their diagnosis and additional 10% progressed to AD. DOs were comparable to subjects with AA in drinking patterns, impairment and stability of diagnostic status. DOs progressed to AD significantly more often than AA. AD was associated with highest levels in all outcomes of interest. Conclusions: The DO status in adolescence and early adulthood is associated with considerable stability, risk of progression and problematic alcohol intake. In consequence, it can be meaningful for the timely identification of early stages of clinically relevant alcohol problems. For subjects with DO status early specific interventions are required.

Objective: We present the prevalence and incidence rates of alcohol, nicotine, and illicit substance use, abuse, and dependence in a sample of German adolescents and young adults. Patterns of onset, cohort trends, and use of various substance classes are also analyzed. Method: A prospective longitudinal epidemiological study with a representative sample of adolescents and young adults (n = 3,021; baseline age range = 14–24 years) was conducted in Munich, Germany. Participants were assessed between 1995 and 1999 with the Munich-Composite International Diagnostic Interview. Results: Cumulative lifetime incidence (up to age 28) of any substance abuse or dependence was 43.8%, and 12-month prevalence of any substance abuse or dependence was 24.4%. The lifetime incidence of nicotine dependence was most frequent (24.8%), followed by alcohol abuse (19.3%) and alcohol dependence (9.2%); 61.7% endorsed the regular use of a substance for at least one circumscribed period during their lifetime. Age-specific incidence rates and age at onset of substance use disorders differed by age cohorts. Furthermore, nicotine dependence was significantly associated with illicit substance use disorders (HR = 2.6, 95% CI 1.7–4.0). An interactive relationship between age, age at onset of nicotine dependence, and subsequent onset of illicit substance use disorders was found. Conclusions: Since the baseline investigation in 1995, high incidence rates of substance use disorders and substance use have been observed in this young German sample. Especially younger cohorts report significantly earlier ages at onset of abuse and dependence. There also seems to be a trend towards a secondary age at onset peak of nicotine dependence after the onset of illicit drug use disorders. Further investigations are needed to study these patterns in younger samples. However, results emphasize the need for a combined prevention of illicit drugs and nicotine dependence. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Alcohol abuse disorders (AUD) represent a serious worldwide health problem with far reaching social, financial, and interpersonal implications. One of the most devastating facets of these disorders is the propensity to relapse following periods of abstinence. Ethanol withdrawal (EWD) is believed to promote relapse by increasing anxiety and craving, and may contribute to the development of cognitive decline associated with long-term dependence. Clinical data suggest that stress also plays a main role in both the development of AUD as well as relapse to drinking. As a physiological stressor, EtOH elevates levels of stress hormones (cortisol in humans, corticosterone (CORT) in the rat). Both CORT and EtOH have been shown to alter the composition, function, and activity of the N-methyl-D-aspartate (NMDA) receptor, and in particular, the NR2B subunit of this receptor. These alterations have been suggested to mediate EWD, which may negatively impact abstinence rates. This synergistic interaction between EtOH and CORT may present a therapeutic target for the treatment of EWD. In fact, data suggest that blocking the glucocorticoid receptor, which is a main target for CORT, with RU-486 could promote abstinence, as treatment with the drug has been shown to reduce consumption and the development dependence, as well as the severity of EWD and the cognitive deficits following EWD. However, these latter effects have not been validated in models of voluntary EtOH consumption. As there is considerable evidence that active versus passive intake can significantly impact neuroadaptations to ethanol this is an important consideration. These studies sought to characterize consumption and evaluate the development of dependence in a chronic voluntary model of intermittent access (IA) to EtOH. CORT plasma levels and protein expression of the glucocorticoid and NR2B receptors were measured during and/or following exposure. Finally, to assess the role of CORT in EtOH consumption and the development of dependence, the glucocorticoid receptor antagonist ORG-34517 was administered during access to EtOH. IA access to 20% EtOH produced varying levels of consumption (2.0-6.7g/kg/24hr exposure) and blood EtOH levels (6.3-116.9 mg/dl), but did not significantly affect food consumption or weight gain. Baseline CORT levels were found to be predictive of subsequent EtOH consumption and levels of consumption were sufficient to elevate CORT levels following one hour of EtOH exposure. Further, IA to EtOH was sufficient to produce dependence, as measured by elevations in the acoustic startle reflex following 26 hours and five days of withdrawal. No alteration in protein expression was observed regarding either the NR2B or glucocorticoid receptors and exposure to ORG-34517 had no effect on consumption or withdrawal.

Zielsetzung: Die Gültigkeit des Modells der Stadien der Veränderung von Prochaska und DiClemente für die stationäre Alkoholentwöhnungstherapie empirisch zu prüfen. Methoden: Reliabilität, Faktorstruktur und Konstruktvalidität der Veränderungsstadienskala (VSS) wurden an Alkoholpatienten querschnittlich (N = 265) und längsschnittlich (N = 108) untersucht. Ergebnisse: Die Reliabilität der VSS fiel befriedigend aus mit Ausnahme der Skala «Precontemplation», die sich auf nicht motivierte Patienten bezieht. Die faktorielle Validität war insbesondere für die Skalen «Contemplation» und «Maintenance» unzureichend. Clusteranalysen ergaben eine nicht modellkonforme Drei-Cluster-Lösung einschließlich «uninvolvierter » Patienten. VSS-Werte waren durchgängig mit der Therapiemotivation korreliert. Prädiktive Validität (Behandlungsdauer, Rückfallvorhersage) konnte nicht belegt werden. Schlussfolgerungen: Der Ansatz bestätigt seinen heuristischen Wert, kann aber noch nicht valide für praktische Entscheidungen in der Alkoholentwöhnungsbehandlung herangezogen werden. Spezifische Modelle für verschiedene Behandlungsgruppen und -settings scheinen Erfolg versprechender. / Aim: The validity of the ”Stages of Change” approach was tested in alcohol inpatient long-term treatment. Methods: Reliability, factor structure, and construct validity of the University of Rhode Island Change Assessment Scale (URICA, German version) was examined using cross-sectional (N = 265) and longitudinal data (N = 108). Results: Scale reliability proved to be satisfying, except for the precontemplation scale. Factorial validity was insufficient for the contemplation and the maintenance scale. Cluster analyses revealed a threecluster solution not in accordance with the model and included a cluster of ”uninvolved patients”. URICA-scores were correlated with therapy motivation, but predictive validity with respect to duration of treatment and prediction of relapse was not confirmed. Conclusions: The model proved to be of heuristic value but is not yet a valid basis for practical decisions. Models which are directed more specifically towards a particular treatment group or setting are expected to be more successful. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Made available in DSpace on 2015-07-22T20:50:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-11-24 / Introdução: A fração lipídica das membranas celulares consiste de ácidos graxos poliinsaturados (PUFAS) e o uso crônico do álcool altera sua composição, modificando a permeabilidade. Portanto, a administração de PUFAS pode ser um potencial tratamento para evitar a compulsão pelo álcool. Metodologia: Este foi um estudo placebo controlado, duplo-cego, randomizado, onde, "PUFAS”, “Naltrexone”, “Naltrexone + PUFAS" e "Placebo", foram administrados por 90 dias, sendo aplicadas escalas para avaliar o craving pelo álcool (OCDS) e a severidade da dependência do álcool (SADD) no início e 90 dias após a administração das substâncias. Resultados: Após 3 meses de seguimento, houve uma melhora significativa ao longo do tempo em relação aos "dias de ingesta", SADD e OCDS em todos os grupos (p <0,001) dentre os 43 pacientes que completaram o estudo. A comparação entre os grupos quanto aos "dias de ingesta" não demonstrou diferença estatisticamente significante (F = 0,71, p = 0,69). O mesmo efeito foi observado para a compulsão (OCDS) (F = 1,08, p = 0,37) e escala de severidade da dependência (SADD) (F = 0,73, p = 0,53). Conclusões: A administração de n-3 e n-6 PUFAS por 3 meses não diferiu significativamente do placebo na redução da quantidade de ingesta de álcool, ou dos escores de OCDS e SADD em um grupo de pacientes dependentes de álcool. Estudos posteriores com mais participantes, ou com tratamento mais prolongado são necessários para avaliar o possível benefício da administração de ácidos graxos poli-insaturados para pacientes dependentes de álcool, quer como monoterapia ou em combinação com o Naltrexone. / TEDE / BV UNIFESP: Teses e dissertações

L’objectif principal de nos études a été de caractériser la pharmacocinétique du baclofène chez le patient alcoolo-dépendant et d’étudier la variation du craving en fonction de l'exposition au baclofène pour objectif de comprendre s’il existait des sujets répondeurs et des sujets non répondeurs. Nous nous sommes intéressés à la sécurité d’emploi du baclofène, à l’influence que pourraient avoir les paramètres démographiques et biologiques ainsi que la consommation de tabac concomitante. Nous avons pu mettre en évidence que le baclofène présentait une pharmacocinétique linéaire avec une relation proportionnelle de 30 à 240 mg par jour avec une importante variabilité interindividuelle. Une modélisation pharmacocinétique/pharmacodynamique par approche de population nous a permis de définir la relation entre l’exposition au baclofène et le craving à l’alcool. Nous avons constaté que le baclofène permettait de diminuer le craving à l’alcool pour l’ensemble des patients traités, et nous avons pu élaborer l’hypothèse qu’il existait deux sous-populations de patients différenciés par leur rapidité de réponse. Bien que chez les patients non-répondeurs (répondeurs tardifs) les taux sanguins de créatinine et de phosphatases alcalines étaient significativement plus élevés laissant supposer que les patients sévèrement malades répondaient moins au traitement, le faible nombre de patients (n=50) et l’absence de placebo ne permettent pas de conclure. Des analyses préliminaires des données de craving à l’alcool et de consommation d’alcool suggèrent qu’il existe une relation entre craving et consommation d’alcool. Des analyses complémentaires sont nécessaires pour confirmer ces résultats. / The main objective of our studies was to characterize the pharmacokinetics of baclofen in alcohol-dependent patients and to investigate the variation of craving as a function of exposure with a secondary objective which was to explore the possible existence of baclofen responders and non-responders. We investigated baclofen safety, the potential influence of demographic and biological parameters as well as the concomitant use of tobacco. We observed that baclofen showed linear pharmacokinetics with a proportional relationship from 30 to 240 mg per day with a high inter-individual variability. A pharmacokinetic/pharmacodynamic population approach has enabled us to define the relationship between baclofen exposure and alcohol craving. A wide inter-individual variability in response was depicted but could not be explained by any of the covariates studied. We found that baclofen could possibly reduce alcohol craving in all the patients treated, and we drew up the hypothesis of two subpopulations of patients differentiated by their speed of response. Although in non-responders (late responders) blood levels of creatinine and alkaline phosphatase were significantly higher than in responders, suggesting that seriously ill patients could be less responsive to baclofen treatment, the low number of patients (n = 50) and the absence of a placebo group renders this results inconclusive. Preliminary analyzes of alcohol craving and alcohol consumption data suggest that a relationship exists between craving and alcohol consumption. Additional analyzes are needed to confirm these results.

First use and initiation of regular alcohol use has been frequently found to start in adolescence. However, only few studies have also investigated how many adolescents proceed during ages 14–24 to harmful drinking or even develop alcohol use disorders. This paper – using the EDSP baseline sample of 3,021 community respondents from the Munich area – examines the prevalence of use, abuse and dependence and investigates the dose/disorder relationship. Alcohol abuse was reported by 9.7% of respondents and alcohol dependence by 6.2%. Men were more likely to report an alcohol disorder than women, prevalence also increased in the older age cohorts. However, even among 14- to 17-year-olds a substantial proportion of respondents report high and regular consumption rates, the occurrence of abuse and dependence criteria and even a full dependence syndrome. There is however only a moderate association between average number of standard drinks consumed with the risk of developing abuse and dependence. In light of the substantial rates among adolescents and young adults the validity of DSM-IV alcohol disorder criteria is discussed.

Objective: We present the prevalence and incidence rates of alcohol, nicotine, and illicit substance use, abuse, and dependence in a sample of German adolescents and young adults. Patterns of onset, cohort trends, and use of various substance classes are also analyzed. Method: A prospective longitudinal epidemiological study with a representative sample of adolescents and young adults (n = 3,021; baseline age range = 14–24 years) was conducted in Munich, Germany. Participants were assessed between 1995 and 1999 with the Munich-Composite International Diagnostic Interview. Results: Cumulative lifetime incidence (up to age 28) of any substance abuse or dependence was 43.8%, and 12-month prevalence of any substance abuse or dependence was 24.4%. The lifetime incidence of nicotine dependence was most frequent (24.8%), followed by alcohol abuse (19.3%) and alcohol dependence (9.2%); 61.7% endorsed the regular use of a substance for at least one circumscribed period during their lifetime. Age-specific incidence rates and age at onset of substance use disorders differed by age cohorts. Furthermore, nicotine dependence was significantly associated with illicit substance use disorders (HR = 2.6, 95% CI 1.7–4.0). An interactive relationship between age, age at onset of nicotine dependence, and subsequent onset of illicit substance use disorders was found. Conclusions: Since the baseline investigation in 1995, high incidence rates of substance use disorders and substance use have been observed in this young German sample. Especially younger cohorts report significantly earlier ages at onset of abuse and dependence. There also seems to be a trend towards a secondary age at onset peak of nicotine dependence after the onset of illicit drug use disorders. Further investigations are needed to study these patterns in younger samples. However, results emphasize the need for a combined prevention of illicit drugs and nicotine dependence. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Thesis (MPA. and Management)) -- University of Limpopo, 2020 / Alcoholism among teenagers has become a major public health issue worldwide. South Africa is amongst the countries that are experiencing this problem. Abuse of alcohol has caused many social ills, namely road crashes, intentional and unintentional injuries, raping, and petty and high end crime in the community. Drinking amongst teenagers could be linked to personal and environmental factors including dysfunctional family structures and alcohol perception of elders in a particular community, which may view it as socially acceptable to drink, among other factors. The purpose of the study is to explore the perception of the community towards alcohol abuse among teenagers in Shayandima Township, Limpopo Province. The current study adopted a convergent mixed research design (both qualitative and quantitative) as well as a self administered questionnaire and semi-structured interview for data collection. A one-on-one interview was also conducted with 12 key informants in order to gather detailed qualitative data on the perception of the community regarding teenage alcohol abuse. In addition, a total of 50 respondents were involved in the quantitative study. They include social workers, ward councillors, members of Shayandima victim empowerment and community police forum members. The findings of this study revealed that there are policies put in place by government to address alcohol abuse by teenagers; however, the liquor sellers and the community members did not adhere to the rules and regulations. Liquor sellers violate the rules by selling liquor to teenagers, while the parents allow teenagers to go and buy liquor and enjoy the very same liquor with them. It was also found that that there was more violence in the community because of alcohol abuse. Parents tend to protect their children rather than supporting local authorities. Teenagers have access to alcohol at any time and any day because parents give them more money to spend, which makes it cheaper for them to buy alcohol. The findings further highlighted that the community was not well informed about the support rendered by those organizations that deal with teenage alcohol abuse. The study recommends that drastic measures should be taken against the liquor sellers who sell alcohol to teenagers. Their liquor licence should be revoked permanently. Government should strengthen their monitoring system regarding the liquor outlets. Only a business area must have liquor outlets, not the township residential areas and near public schools. Community-based organisations should be promoted to enhance community awareness and act against teenage alcohol abuse. Key words: Alcohol, Teenage, Alcohol Abuse, Community Perception, Shayandima Township