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An alcohol withdrawal test battery measuring multiple behavioral symptoms in mice.

ABSTRACT: Despite acceptance that risk for alcohol-use disorder (AUD) has a large genetic component, the identification of genes underlying various components of risk for AUD has been hampered in humans, in part by the heterogeneity of expression of the phenotype. One aspect of AUD is physical dependence. Alcohol withdrawal is a serious consequence of alcohol dependence with multiple symptoms, many of which are seen in multiple species, and can be experienced over a wide-ranging time course. In the present three studies, we developed a battery of withdrawal tests in mice, examining behavioral symptoms from multiple domains that could be measured over time. To permit eventual use of the battery in different strains of mice, we used male and female mice of a genetically heterogeneous stock developed from intercrossing eight inbred strains. Withdrawal symptoms were assessed using commonly used tests after administration of ethanol in vapor for 72 continuous hours. We found significant effects of ethanol withdrawal versus air-breathing controls on nearly all symptoms, spanning 4 days following ethanol vapor inhalation. Withdrawal produced hypothermia, greater neurohyperexcitability (seizures and tremor), anxiety-like behaviors using an apparatus (such as reduced transitions between light and dark compartments), anhedonia (reduced sucrose preference), Straub tail, backward walking, and reductions in activity; however, there were no changes in thermal pain sensitivity, hyper-reactivity to handling, or anxiety-like emergence behaviors in other apparatus. Using these data, we constructed a refined battery of withdrawal tests. Individual differences in severity of withdrawal among different tests were weakly correlated at best. This battery should be useful for identifying genetic influences on particular withdrawal behaviors, which should reflect the influences of different constellations of genes.

SUBMITTER: Metten P

PROVIDER: S-EPMC5839916 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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An alcohol withdrawal test battery measuring multiple behavioral symptoms in mice.

Metten Pamela P Schlumbohm Jason P JP Huang Lawrence C LC Greenberg Gian D GD Hack Wyatt R WR Spence Stephanie E SE Crabbe John C JC

Alcohol (Fayetteville, N.Y.) 20170906

Despite acceptance that risk for alcohol-use disorder (AUD) has a large genetic component, the identification of genes underlying various components of risk for AUD has been hampered in humans, in part by the heterogeneity of expression of the phenotype. One aspect of AUD is physical dependence. Alcohol withdrawal is a serious consequence of alcohol dependence with multiple symptoms, many of which are seen in multiple species, and can be experienced over a wide-ranging time course. In the presen ...[more]

PMID: 29427828

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Project description:BackgroundAlcohol use disorder (AUD) is a major problem of our society and is often characterized and worsened by relapse. Prolonged alcohol exposure leads to numerous biochemical alterations that, upon cessation of alcohol intake, cause an array of immediate and lasting withdrawal symptoms. Acute withdrawal and neuroinflammation can be harmful in themselves, and lasting withdrawal symptoms contribute to relapse. Here, we conducted an initial feasibility study assessing several behavioral and neurochemical factors in female C3H/HeNRj (C3H) and C57BL/6JRj (B6) mice to determine which strain showed the clearest alcohol withdrawal symptoms during long-term abstinence and neurochemical alterations following re-exposure.MethodsFemale C3H and B6 mice (n = 12 per group/strain) were intermittently exposed to alcohol-containing or control liquid diets for 3 weeks. Acute and prolonged withdrawal symptoms were assessed over a period of 3 weeks using a battery of behavioral test, comprised of alcohol self-administration, anhedonia, hyperalgesia, anxiety-like and depressive-like disturbances. Brain inflammation was measured by multiplex cytokine assay. Monoamine levels in the hippocampus and striatum, as well as exploratory analyses of cations levels in the cerebellum, were assessed by High-Performance Liquid Chromatography (HPLC).ResultsBoth C3H and B6 alcohol-exposed mice displayed decreased saccharin intake or preference and higher stress levels assessed by ultrasonic vocalizations (USVs) recordings. B6 but not C3H alcohol-exposed mice also exhibited a slower decline of alcohol oral self-administration (OSA), hyperalgesia, elevated brain TNF-α and elevated serotonin turnover.ConclusionOur findings highlight the suitability of the B6 strain to study the behavioral and neurochemical alterations caused by alcohol withdrawal and the potential efficacy of experimental treatments, not only in early detoxification, but also in prolonged abstinence. The feasibility of these assays is important because long-lasting withdrawal symptoms are often the main cause of relapse in alcohol-dependent patients.

Project description:ObjectiveAlcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of alcohol craving and mood, anxiety, and sleep disturbances, which are predictive of poor treatment outcomes. The authors examined whether alcohol withdrawal symptoms moderate the efficacy of prazosin in reducing alcohol intake and associated secondary outcomes.MethodsA 12-week, double-blind, randomized, controlled proof-of-concept trial of prazosin (16 mg/day, with a 2-week titration) was conducted in community-recruited adults with current alcohol dependence (N=100) with varying levels of alcohol withdrawal symptoms assessed at treatment entry. Primary outcomes were daily self-reported drinking days and heavy drinking days, and secondary outcomes were average drinks/day and mood, anxiety, craving, and sleep quality ratings.ResultsModified intent-to-treat analyses indicated a significant interaction of alcohol withdrawal symptom score by treatment by full-dose treatment period (weeks 3-12) for drinking days, heavy drinking days, and average drinks/day. By week 12, participants with high alcohol withdrawal symptoms on prazosin reported 7.07% heavy drinking days and 27.46% drinking days, while those on placebo had 35.58% heavy drinking days and 58.47% drinking days (heavy drinking days: odds ratio=0.14, 95% CI=0.058, 0.333; drinking days: odds ratio=0.265, 95% CI=0.146, 0.481). No such benefit of prazosin was observed in those reporting low or no alcohol withdrawal symptoms. Individuals with high alcohol withdrawal symptoms on prazosin compared with placebo also showed significantly improved anxiety, depression, and alcohol craving over the course of the trial.ConclusionsThe findings indicate that alcohol withdrawal symptoms are a significant moderator of prazosin treatment response for alcohol use outcomes and for associated symptoms of alcohol craving, anxiety, and mood symptoms. These data support further evaluation of alcohol withdrawal symptoms as a prognostic indicator of prazosin's efficacy in the treatment of AUD.

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An alcohol withdrawal test battery measuring multiple behavioral symptoms in mice.

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An alcohol withdrawal test battery measuring multiple behavioral symptoms in mice.

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