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Triple monoamine uptake inhibitors demonstrate a pharmacologic association between excessive drinking and impulsivity in high-alcohol-preferring (HAP) mice.

ABSTRACT: Approximately 30% of current drinkers in the United States drink excessively, and are referred to as problem/hazardous drinkers. These individuals, who may not meet criteria for alcohol abuse or dependence, comprise binge, heavy drinkers, or both. Given their high prevalence, interventions that reduce the risk of binge and heavy drinking have important public health implications. Impulsivity has been repeatedly associated with excessive drinking in the clinical literature. As impulsivity is correlated with, and may play a critical role in, the initiation and maintenance of excessive drinking, this behavior may be an important target for therapeutic intervention. Hence, a better understanding of pharmacological treatments capable of attenuating excessive drinking and impulsivity may markedly improve clinical outcomes. The high-alcohol-preferring (HAP) mice represent a strong rodent model to study the relationship between impulsivity and excessive alcohol drinking, as recent evidence indicates they consume high levels of alcohol throughout their active cycle and are innately impulsive. Using this model, the present study demonstrates that the triple monoamine uptake inhibitors (TUIs) amitifadine and DOV 102, 677 effectively attenuate binge drinking, heavy drinking assessed via a 24-hour free-choice assay, and impulsivity measured by the delay discounting procedure. In contrast, 3-PBC, a GABA-A ?1 preferring ligand with mixed agonist-antagonist properties, attenuates excessive drinking without affecting impulsivity. These findings suggest that in HAP mice, monoamine pathways may predominate as a common mechanism underlying impulsivity and excessive drinking, while the GABAergic system may be more salient in regulating excessive drinking. We further propose that TUIs such as amitifadine and DOV 102, 677 may be used to treat the co-occurrence of impulsivity and excessive drinking.

SUBMITTER: O'Tousa DS

PROVIDER: S-EPMC3984927 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Triple monoamine uptake inhibitors demonstrate a pharmacologic association between excessive drinking and impulsivity in high-alcohol-preferring (HAP) mice.

O'Tousa David S DS Warnock Kaitlin T KT Matson Liana M LM Namjoshi Ojas A OA Linn Michael Van MV Tiruveedhula Veera Venkata VV Halcomb Meredith E ME Cook James J Grahame Nicholas J NJ June Harry L HL

Addiction biology 20131013 2

Approximately 30% of current drinkers in the United States drink excessively, and are referred to as problem/hazardous drinkers. These individuals, who may not meet criteria for alcohol abuse or dependence, comprise binge, heavy drinkers, or both. Given their high prevalence, interventions that reduce the risk of binge and heavy drinking have important public health implications. Impulsivity has been repeatedly associated with excessive drinking in the clinical literature. As impulsivity is corr ...[more]

PMID: 24118509

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Project description:BackgroundImpulsivity is genetically correlated with, and precedes, addictive behaviors and alcoholism. If impulsivity or attention is causally related to addiction, certain pharmacological manipulations of impulsivity and/or attention may affect alcohol drinking, and vice versa. The current studies were designed to explore the relationship among impulsivity, drinking, and vigilance in selectively bred High Alcohol Preferring (HAP) mice, a line that has previously demonstrated both high impulsivity and high alcohol consumption. Amphetamine, naltrexone, and memantine were tested in a delay discounting (DD) task for their effects on impulsivity and vigilance. The same drugs and doses were also assessed for effects on alcohol drinking in a 2-bottle choice test.MethodsHAP mice were subjected to a modified version of adjusting amount DD using 0.5-second and 10-second delays to detect decreases and increases, respectively, in impulsive responding. In 2 experiments, mice were given amphetamine (0.4, 0.8, or 1.2 mg/kg), naltrexone (3 and 10 mg/kg), and memantine (1 and 5 mg/kg) before DD testing. Another pair of studies used scheduled access, 2-bottle choice drinking to assess effects of amphetamine (0.4, 1.2, or 3.0 mg/kg), naltrexone (3 and 10 mg/kg), and memantine (1 and 5 mg/kg) on alcohol consumption.ResultsAmphetamine dose-dependently reduced impulsivity and vigilance decrement in DD, but similar doses left alcohol drinking unaffected. Naltrexone and memantine decreased alcohol intake at doses that did not affect water drinking but had no effects on impulsivity or vigilance decrement in the DD task.ConclusionsContrary to our hypothesis, none of the drugs tested here, while effective on either alcohol drinking or impulsivity, decreased both behaviors. These findings suggest that the genetic association between drinking and impulsivity observed in this population is mediated by mechanisms other than those targeted by the drugs tested in these studies.

Project description:Numerous work-related drinking mechanisms have been posited and, oftentimes, examined in isolation. We combined data from over 100 occupational attributes into several factors and tested the association of these factors with measures of alcohol use. We used the NLSY79 2006 wave, a U.S. representative sample of 6426 workers ages 41 to 49 and the 2006 Occupational Information Network database (O*NET), a nationally representative sample of nearly 1000 occupations. We conducted exploratory factor analysis on 119 occupational attributes and found three independent workplace characteristics - physical demands, job autonomy, and social engagement - explained the majority of the variation. We then tested the association of these composite attributes with three drinking measures, before and after adjusting for gender, race/ethnicity, and a measure of human capital using count data models. We then stratified by gender and repeated our analyses. Men working in occupations with a one standard deviation higher level of physical demand (e.g. construction) reported a higher number of heavy drinking occasions (+20%, p < 0.05). Job autonomy was not significantly associated with measures of alcohol use and when the combined association of higher levels of physical demand and lower levels of job autonomy was examined, modest support for job strain as a mechanism for work-related alcohol consumption was found. In our pooled sample, working in occupations with one standard deviation higher levels of social engagement was associated with lower numbers of drinking days (-9%, p < 0.05) after adjustment. Physical demand and social engagement were associated with alcohol consumption measures but these relationships varied by workers' gender. Future areas of research should include confirmatory analyses using other waves of O*Net data and replicating the current analysis in other samples of workers. If our results are validated, they suggest male workers in high physical demand occupations could be targets for intervention.

Project description:Increased levels of impulsivity are associated with increased illicit drug use and alcoholism. Previous research in our laboratory has shown that increased levels of delay discounting (a decision-making form of impulsivity) are related to appetitive processes governing alcohol self-administration as opposed to purely consummatory processes. Specifically, the high-seeking/high-drinking alcohol-preferring P rats showed increased delay discounting compared to nonselected Long Evans rats (LE) whereas the high-drinking/moderate-seeking HAD2 rats did not. The P rats also displayed a perseverative pattern of behavior such that during operant alcohol self-administration they exhibited greater resistance to extinction.One explanation for the previous findings is that P rats have a deficit in response inhibition. This study followed up on this possibility by utilizing a countermanding paradigm (stop signal reaction time [SSRT] task) followed by operant self-administration of alcohol across increasing fixed ratio requirements (FR; 1, 2, 5, 10, and 15 responses). In separate animals, 24-hour access 2-bottle choice (10% EtOH vs. water) drinking was assessed.In the SSRT task, P rats exhibited an increased SSRT compared to both LE and HAD2 rats indicating a decrease in behavioral inhibition in the P rats. Also, P rats showed increased operant self-administration across all FRs and the greatest increase in responding with increasing FR requirements. Conversely, the HAD2 and LE had shorter SSRTs and lower levels of operant alcohol self-administration. However, for 2-bottle choice drinking HAD2s and P rats consumed more EtOH and had a greater preference for EtOH compared to LE.These data extend previous findings showing the P rats to have increased delay discounting (decision-making impulsivity) and suggest that P rats also have a lack of behavioral inhibition (motor impulsivity). This supports the notion that P rats are a highly impulsive as well as "high-seeking" model of alcoholism, and that the HAD2s' elevated levels of alcohol consumption are not mediated via appetitive processes or impulsivity.

Project description:BackgroundBinge drinking (BD) refers to a pattern of alcohol consumption characterized by the consumption of large amounts of alcohol in a short period of time followed by periods of abstinence. This drinking pattern is prevalent worldwide, mainly among young people. Excessive alcohol consumption is the spectrum of consumption patterns that may have or have had health consequences, and includes the concepts of risky alcohol use, harmful alcohol use and alcohol dependence according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), the latter two are currently grouped into alcohol use disorder (AUD) according to the fifth edition of the DSM (DSM-5). Due to the high prevalence of BD among young people, especially university students, as well as the important consequences of its practice, a study was conducted to evaluate excessive alcohol consumption and its relationship with the practice of BD in university students.MethodsA cross-sectional study was conducted among students (aged 18-30 years) enrolled in the academic year 2018-2019 at the Faculty of Nursing at a university in northern Spain. Data collection included sociodemographic information, and alcohol use information, collected using a semi-structured questionnaire. To measure the excessive alcohol consumption, this study used the Alcohol Use Disorders Identification Test (AUDIT).ResultsA total of 142 participants were included, of which 88.03% were women. Up to 38.03% were classified as BD. Up to 14.77% of non-BD participants and 66.67% of BD participants were classified as risky drinkers (AUDIT Total geq 8 in men or geq 6 in women) (p < 0.001). Up to 3.41% of the non-BD and 24.07% of the BD were drinkers with harmful alcohol use and probable alcohol dependence (AUDIT Total geq 13) (p < 0.001). A total of 5.68% of non-BD and 42.59% of BD were AUD drinkers (AUDIT Total geq 9 in males or geq 8 in females) (p < 0.001). In addition, statistically significant differences were found between the BD and non-BD groups in the responses to each of the AUDIT items, as well as in the total score and also in the scores of the three domains of the questionnaire.ConclusionsExcessive alcohol consumption is frequent among university students, especially among those who practice BD.

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Triple monoamine uptake inhibitors demonstrate a pharmacologic association between excessive drinking and impulsivity in high-alcohol-preferring (HAP) mice.

Publications

Triple monoamine uptake inhibitors demonstrate a pharmacologic association between excessive drinking and impulsivity in high-alcohol-preferring (HAP) mice.

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