Neurometabolite Levels in Alcohol Use Disorder Patients During Baclofen Treatment and Prediction of Relapse to Heavy Drinking

Background and Aims: Baclofen, a GABAB agonist, is used as a treatment for alcohol dependence. We aimed to examine brain metabolites following administration of baclofen or placebo in alcohol dependent individuals enrolled in a randomized placebo-controlled trial.Methods: Participants included 31 alcohol dependent individuals (recent drinking: N = 16; and abstinent: N = 15) who had received daily baclofen (BAC 30–75 mg = 20) or placebo (PL = 11) for at least 2 weeks (average 17 days). Using in vivo proton magnetic resonance spectroscopy (1H-MRS), spectra from the right parietal lobe were analyzed to obtain measures of GABA, Glutamate (Glu), Glutathione (GSH) and N-Acetyl Apartate (NAA) 120 min following administration of PL or BAC.Results: When weighting alcohol dependent participants according to recent alcohol consumption (within 24 h), there were significant differences between BAC and PL on parietal concentrations of GSH (p < 0.01) and NAA (p < 0.05). Multiple linear regression revealed a significant predictive effect of GSH on heavy drinking days at 12 weeks follow-up (Model: F = 14.28, R2 = 0.85; GSH: B = −1.22, p = 0.01) and also percentage days abstinent at 12 weeks follow-up (Model: F = 6.50, R2 = 0.72; GSH: B = 0.99, p = 0.06).Conclusion: Our data provide preliminary evidence that the effect of baclofen may be mediated by increased parietal concentrations of the antioxidant GSH and NAA in recently drinking alcohol dependent patients. GSH/Cr levels were also predictive of improved drinking outcomes in the trial and suggests a role for neural oxidative stress in alcohol use disorder

New Australian guidelines for the treatment of alcohol problems: an overview of recommendations

Summary of recommendations and levels of evidence Chapter 2: Screening and assessment for unhealthy alcohol use Screening Screening for unhealthy alcohol use and appropriate interventions should be implemented in general practice (Level A), hospitals (Level B), emergency departments and community health and welfare settings (Level C). Quantity–frequency measures can detect consumption that exceeds levels in the current Australian guidelines (Level B). The Alcohol Use Disorders Identification Test (AUDIT) is the most effective screening tool and is recommended for use in primary care and hospital settings. For screening in the general community, the AUDIT-C is a suitable alternative (Level A). Indirect biological markers should be used as an adjunct to screening (Level A), and direct measures of alcohol in breath and/or blood can be useful markers of recent use (Level B). Assessment Assessment should include evaluation of alcohol use and its effects, physical examination, clinical investigations and collateral history taking (Level C). Assessment for alcohol-related physical problems, mental health problems and social support should be undertaken routinely (GPP). Where there are concerns regarding the safety of the patient or others, specialist consultation is recommended (Level C). Assessment should lead to a clear, mutually acceptable treatment plan which specifies interventions to meet the patient’s needs (Level D). Sustained abstinence is the optimal outcome for most patients with alcohol dependence (Level C). Chapter 3: Caring for and managing patients with alcohol problems: interventions, treatments, relapse prevention, aftercare, and long term follow-up Brief interventions Brief motivational interviewing interventions are more effective than no treatment for people who consume alcohol at risky levels (Level A). Their effectiveness compared with standard care or alternative psychosocial interventions varies by treatment setting. They are most effective in primary care settings (Level A). Psychosocial interventions Cognitive behaviour therapy should be a first-line psychosocial intervention for alcohol dependence. Its clinical benefit is enhanced when it is combined with pharmacotherapy for alcohol dependence or an additional psychosocial intervention (eg, motivational interviewing) (Level A). Motivational interviewing is effective in the short term and in patients with less severe alcohol dependence (Level A). Residential rehabilitation may be of benefit to patients who have moderate-to-severe alcohol dependence and require a structured residential treatment setting (Level D). Alcohol withdrawal management Most cases of withdrawal can be managed in an ambulatory setting with appropriate support (Level B). Tapering diazepam regimens (Level A) with daily staged supply from a pharmacy or clinic are recommended (GPP). Pharmacotherapies for alcohol dependence Acamprosate is recommended to help maintain abstinence from alcohol (Level A). Naltrexone is recommended for prevention of relapse to heavy drinking (Level A). Disulfiram is only recommended in close supervision settings where patients are motivated for abstinence (Level A). Some evidence for off-label therapies baclofen and topiramate exists, but their side effect profiles are complex and neither should be a first-line medication (Level B). Peer support programs Peer-led support programs such as Alcoholics Anonymous and SMART Recovery are effective at maintaining abstinence or reductions in drinking (Level A). Relapse prevention, aftercare and long-term follow-up Return to problematic drinking is common and aftercare should focus on addressing factors that contribute to relapse (GPP). A harm-minimisation approach should be considered for patients who are unable to reduce their drinking (GPP). Chapter 4: Providing appropriate treatment and care to people with alcohol problems: a summary for key specific populations Gender-specific issues Screen women and men for domestic abuse (Level C). Consider child protection assessments for caregivers with alcohol use disorder (GPP). Explore contraceptive options with women of reproductive age who regularly consume alcohol (Level B). Pregnant and breastfeeding women Advise pregnant and breastfeeding women that there is no safe level of alcohol consumption (Level B). Pregnant women who are alcohol dependent should be admitted to hospital for treatment in an appropriate maternity unit that has an addiction specialist (GPP). Young people Perform a comprehensive HEEADSSS assessment for young people with alcohol problems (Level B). Treatment should focus on tangible benefits of reducing drinking through psychotherapy and engagement of family and peer networks (Level B). Aboriginal and Torres Strait Islander peoples Collaborate with Aboriginal or Torres Strait Islander health workers, organisations and communities, and seek guidance on patient engagement approaches (GPP). Use validated screening tools and consider integrated mainstream and Aboriginal or Torres Strait Islander-specific approaches to care (Level B). Culturally and linguistically diverse groups Use an appropriate method, such as the “teach-back” technique, to assess the need for language and health literacy support (Level C). Engage with culture-specific agencies as this can improve treatment access and success (Level C). Sexually diverse and gender diverse populations Be mindful that sexually diverse and gender diverse populations experience lower levels of satisfaction, connection and treatment completion (Level C). Seek to incorporate LGBTQ-specific treatment and agencies (Level C). Older people All new patients aged over 50 years should be screened for harmful alcohol use (Level D). Consider alcohol as a possible cause for older patients presenting with unexplained physical or psychological symptoms (Level D). Consider shorter acting benzodiazepines for withdrawal management (Level D). Cognitive impairment Cognitive impairment may impair engagement with treatment (Level A). Perform cognitive screening for patients who have alcohol problems and refer them for neuropsychological assessment if significant impairment is suspected (Level A). Summary of key recommendations and levels of evidence Chapter 5: Understanding and managing comorbidities for people with alcohol problems: polydrug use and dependence, co-occurring mental disorders, and physical comorbidities Polydrug use and dependence Active alcohol use disorder, including dependence, significantly increases the risk of overdose associated with the administration of opioid drugs. Specialist advice is recommended before treatment of people dependent on both alcohol and opioid drugs (GPP). Older patients requiring management of alcohol withdrawal should have their use of pharmaceutical medications reviewed, given the prevalence of polypharmacy in this age group (GPP). Smoking cessation can be undertaken in patients with alcohol dependence and/or polydrug use problems; some evidence suggests varenicline may help support reduction of both tobacco and alcohol consumption (Level C). Co-occurring mental disorders More intensive interventions are needed for people with comorbid conditions, as this population tends to have more severe problems and carries a worse prognosis than those with single pathology (GPP). The Kessler Psychological Distress Scale (K10 or K6) is recommended for screening for comorbid mental disorders in people presenting for alcohol use disorders (Level A). People with alcohol use disorder and comorbid mental disorders should be offered treatment for both disorders; care should be taken to coordinate intervention (Level C). Physical comorbidities Patients should be advised that alcohol use has no beneficial health effects. There is no clear risk-free threshold for alcohol intake. The safe dose for alcohol intake is dependent on many factors such as underlying liver disease, comorbidities, age and sex (Level A). In patients with alcohol use disorder, early recognition of the risk for liver cirrhosis is critical. Patients with cirrhosis should abstain from alcohol and should be offered referral to a hepatologist for liver disease management and to an addiction physician for management of alcohol use disorder (Level A). Alcohol abstinence reduces the risk of cancer and improves outcomes after a diagnosis of cancer (Level A)

Multiple perspectives on self-regulation in alcohol use disorder: executive functioning, neuroimaging and psychophysiology

Empirical thesis.Bibliography: pages 213-260.Chapter One. General introduction -- Chapter Two. Executive functioning and dysregulated drinking history are associated with regulation of alcohol cue responses in non-treatment-seeking drinkers -- Chapter Three. Regulation of alcohol cue-elicited responses in alcoholic liver disease and alcohol dependent drinkers during a cue reactivity task -- Chapter Four. Impaired decision-making and reduced somatic responses indicating expectation of risky choices during the Iowa Gambling Task in severe alcohol use disorderD -- Chapter Five. Neural correlates of alcohol cue-induced brain activation and neuropsychological executive functioning measures in individuals with alcohol dependence -- Chapter Six. General discussion -- References -- Appendices.Reduced ability to regulate deleterious behaviours can lead to negative social, health, and financial outcomes. Individuals with alcohol use disorder that continue to drink despite adverse consequences from their drinking demonstrate dysregulated drinking behaviour, potentially due to difficulty in appropriate self-regulation. Identifying the factors that may be integral in appropriate regulation of responses to alcohol cues may help us better understand the underlying mechanisms involved in self-regulation in these dysregulated individuals. Elucidating the factors involved in the regulation of impulsive, motivational drives inherent in alcohol use disorder is important to inform and augment current frameworks, which do not yet adequately explain dysregulated behaviour within this complex and multifaceted disorder.Thus, the aim of thesis was to empirically examine the regulation of responses to alcohol cues and influencing factors in alcohol use disorder. A diverse methodology of neuropsychological, psychophysiological and neuroimaging techniques was applied to comprehensively evaluate regulation across various time periods surrounding cue presentation, to assess the influence of components, such as executive functioning, in appropriate regulation, and to identify overlapping evidence of underlying regulatory processes and influencing factors in a range of dysregulated alcohol use disorder samples.Four separate studies were conducted. The first applied an influential theoretical framework of executive functioning to demonstrate discrete executive functioning domains were uniquely associated with the regulation of alcohol cue-elicited responses as indicated by physiological indices in non-treatment-seeking drinkers. The second further investigated these associations using the same methodology in more severely dysregulated alcohol use disorder samples—individuals with alcoholic liver disease and alcohol dependence—and showed overall difficulties in regulation of responses in these samples that were not related to executive functioning ability. The third used the same dysregulated samples to examine whether reduced capacity for incorporating previous negative feedback leads to impaired decision-making processes regarding drinking, and found reduced physiological responses to risky choices with negative outcomes and decision-making deficits in these samples. The final study used functional neuroimaging techniques to find converging reduced neural activation in prefrontal regions related to regulation of alcohol cue responses, and worse executive functioning and dysregulated drinking measures in an alcohol dependent sample.Taken together, this thesis advances our understanding of the integral components that may underlie the progression and maintenance of alcohol use disorder. This body of work contributes to the literature involved in elucidating the role of self-regulation and influencing factors in alcohol use disorder, through a convergence of neurocircuitry and underlying neurocognitive mechanisms that is essential to advance our understanding of key processes of regulation in alcohol use disorder and better inform treatment approaches.Mode of access: World wide web1 online resource (ix, 276 pages) graphs, table

Multiple perspectives on self-regulation in alcohol use disorder: executive functioning, neuroimaging and psychophysiology

Empirical thesis.Bibliography: pages 213-260.Chapter One. General introduction -- Chapter Two. Executive functioning and dysregulated drinking history are associated with regulation of alcohol cue responses in non-treatment-seeking drinkers -- Chapter Three. Regulation of alcohol cue-elicited responses in alcoholic liver disease and alcohol dependent drinkers during a cue reactivity task -- Chapter Four. Impaired decision-making and reduced somatic responses indicating expectation of risky choices during the Iowa Gambling Task in severe alcohol use disorderD -- Chapter Five. Neural correlates of alcohol cue-induced brain activation and neuropsychological executive functioning measures in individuals with alcohol dependence -- Chapter Six. General discussion -- References -- Appendices.Reduced ability to regulate deleterious behaviours can lead to negative social, health, and financial outcomes. Individuals with alcohol use disorder that continue to drink despite adverse consequences from their drinking demonstrate dysregulated drinking behaviour, potentially due to difficulty in appropriate self-regulation. Identifying the factors that may be integral in appropriate regulation of responses to alcohol cues may help us better understand the underlying mechanisms involved in self-regulation in these dysregulated individuals. Elucidating the factors involved in the regulation of impulsive, motivational drives inherent in alcohol use disorder is important to inform and augment current frameworks, which do not yet adequately explain dysregulated behaviour within this complex and multifaceted disorder.Thus, the aim of thesis was to empirically examine the regulation of responses to alcohol cues and influencing factors in alcohol use disorder. A diverse methodology of neuropsychological, psychophysiological and neuroimaging techniques was applied to comprehensively evaluate regulation across various time periods surrounding cue presentation, to assess the influence of components, such as executive functioning, in appropriate regulation, and to identify overlapping evidence of underlying regulatory processes and influencing factors in a range of dysregulated alcohol use disorder samples.Four separate studies were conducted. The first applied an influential theoretical framework of executive functioning to demonstrate discrete executive functioning domains were uniquely associated with the regulation of alcohol cue-elicited responses as indicated by physiological indices in non-treatment-seeking drinkers. The second further investigated these associations using the same methodology in more severely dysregulated alcohol use disorder samples—individuals with alcoholic liver disease and alcohol dependence—and showed overall difficulties in regulation of responses in these samples that were not related to executive functioning ability. The third used the same dysregulated samples to examine whether reduced capacity for incorporating previous negative feedback leads to impaired decision-making processes regarding drinking, and found reduced physiological responses to risky choices with negative outcomes and decision-making deficits in these samples. The final study used functional neuroimaging techniques to find converging reduced neural activation in prefrontal regions related to regulation of alcohol cue responses, and worse executive functioning and dysregulated drinking measures in an alcohol dependent sample.Taken together, this thesis advances our understanding of the integral components that may underlie the progression and maintenance of alcohol use disorder. This body of work contributes to the literature involved in elucidating the role of self-regulation and influencing factors in alcohol use disorder, through a convergence of neurocircuitry and underlying neurocognitive mechanisms that is essential to advance our understanding of key processes of regulation in alcohol use disorder and better inform treatment approaches.Mode of access: World wide web1 online resource (ix, 276 pages) graphs, table

Novel behavioural characteristics of the APPSwe/PS1ΔE9 transgenic mouse model of Alzheimer\u27s disease

In order to better understand animal models of Alzheimer\u27s disease, novel phenotyping strategies have been established for transgenic mouse models. In line with this, the current study characterised male APPxPS1 transgenic mice on mixed C57BL/6JxC3H/HeJ background for the first time for social recognition memory, sensorimotor gating, and spatial memory using the cheeseboard test as an alternative to the Morris water maze. Furthermore, locomotion, anxiety, and fear conditioning were evaluated in transgenic and wild type-like animals. APPxPS1 males displayed task-dependent hyperlocomotion and anxiety behaviours and exhibited social recognition memory impairments compared to wild type-like littermates. Spatial learning and memory, fear conditioning, and sensorimotor gating were unaffected in APPxPS1 transgenic mice. In conclusion, this study describes for the first time social recognition memory deficits in male APPxPS1 mice and suggests that spatial learning and memory deficits reported in earlier studies are dependent on the sex and genetic background of the APPxPS1 mouse line used. Furthermore, particular test conditions of anxiety and spatial memory paradigms appear to impact on the behavioural response of this transgenic mouse model for Alzheimer\u27s disease

The Moderating Effects of Impulsivity and Tension-Reduction Alcohol Expectancies on Social Anxiety and Alcohol Use

Comorbidity between social anxiety disorder and alcohol use disorders is common, however the mechanisms underlying this link are still unclear. Two theorized mechanisms underlying the association between social anxiety and alcohol use are impulsivity and tension-reduction alcohol expectancies (TRAEs), reflecting alcohol use for negative affect removal. The current study was the first to experimentally examine this relationship through controlling state-anxiety and alcohol craving. Forty-nine students completed an anticipatory speech task to induce anxiety, during which they were randomly allocated to conditions with exposure to the presence of alcohol (n = 24) or soft drink (n = 25). Anxiety induction was manipulated successfully although craving was not. Unexpectedly, no effect was found for impulsivity or TRAEs and their interaction with condition on shifts in craving, sympathetic reactivity or parasympathetic reactivity from baseline to post-condition exposure. TRAEs also showed no effect on self-rated anxiety. These unexpected results were theorized to stem from the performance nature of the speech task, alcohol-resistant sample characteristics and power issues. As expected, impulsivity was found to interact with state anxiety over time in the presence of alcohol, however no UPPS impulsivity subscales exhibited significant effects. Further analysis of bivariate correlations and regression coefficients suggested positive urgency and sensation seeking to unexpectedly increase anxiety in the presence of alcohol. Negative urgency was associated with a decrease in anxiety in the presence of alcohol as expected, reflecting alcohol use for negative affect removal. These findings suggest the need for impulsivity to be viewed as a multidimensional construct with individual facets presenting differently within the social anxiety-alcohol use relationship, and specifically, the potential importance of negative urgency in this relationship

Do individually ventilated cage systems generate a problem for genetic mouse model research?

Technological developments over recent decades have produced a novel housing system for laboratory mice, so-called 'individually ventilated cage' (IVC) systems. IVCs present a cage environment which is different to conventional filter-top cages (FILTER). Nothing is known about the consequences of IVC housing on genetic mouse models, despite studies reporting IVC-mediated changes to the phenotypes of inbred mouse strains. Thus, in this study, we systematically compared the established behavioural phenotype of a validated mouse model for the schizophrenia risk gene neuregulin 1 (TM Nrg1 HET) kept in FILTER housing with Nrg1 mutant mice raised in IVC systems. We found that particular schizophrenia-relevant endophenotypes of TM Nrg1 HETs which had been established and widely published using FILTER housing were altered when mice were raised in IVC housing. IVCs diminished the schizophrenia-relevant prepulse inhibition deficit of Nrg1 mutant males. Furthermore, IVC housing had a sex-dependent moderate effect on the locomotive phenotype of Nrg1 mice across test paradigms. Behavioural effects of IVC housing were less prominent in female mice. Thus, transferring the breeding colony of mouse mutants from FILTER to IVC systems can shift disease-relevant behaviours and therefore challenge the face validity of these mice. Researchers facing an upgrade of their mouse breeding or holding facilities to IVC systems must be aware of the potential impact this upgrade might have on their genetic mouse models. Future publications should provide more details on the cage system used to allow appropriate data comparison across research sites

Cognitive Impairment

This chapter provides an overview of treatment options and approaches for patients with cognitive impairment. The prevalence of cognitive impairment (CI) in people seeking treatment for alcohol use disorder (AUD) is high (up to two thirds with some form of impairment). Impaired cognitive functioning is related to poorer treatment retention and increased risk of relapse. Early assessment and ongoing monitoring of cognitive status is therefore essential for appropriate treatment planning and to maximise likelihood of treatment success

Single high dose treatment with methotrexate causes long-lasting cognitive dysfunction in laboratory rodents

Clinical studies have suggested that cognitive impairment due to chemotherapy persists long after treatment cessation. While animal studies have similarly found impairments in cognition due to chemotherapy, these studies are limited as they only assess the acute or extremely short-term effects of chemotherapy on cognition (e.g. within 1 month of treatment). Male hooded Wistar rats (N = 22) received either a high dose of methotrexate (MTX: 250 mg/kg i.p.) or physiological saline. Cognitive performance was evaluated acutely at 2 weeks, and up to 8 months post injection using the Morris water maze, Novel object recognition task, and an instrumental go/no-go task to assess discrimination learning. MTX-treated rats displayed impaired novel object recognition compared to controls at 11, 95, and 255 days after treatment. MTX rats were able to learn the hidden spatial location of a platform 22 days after treatment. When tested again after a 95-day retention interval, MTX rats showed impaired spatial memory compared to controls, but were subsequently able to re-learn the task. Finally, MTX-treated rats showed considerable difficulty learning to inhibit their behaviour in an instrumental discrimination task. These results show that chemotherapy produces persistent but subtle cognitive deficits in laboratory rodents that vary with time post treatment.7 page(s

Behavioural consequences of IVC cages on male and female C57BL/6J mice

Recent developments in the technology to breed and house laboratory rodents for medical research has produced individually ventilated cage (IVC) systems. These IVC systems produce a cage environment significantly different to conventional cages. As it is not known in detail whether housing mice in IVCs impacts on their baseline and drug-induced behaviours compared to mice of conventional filter-top cages a comprehensive multi-tiered phenotyping strategy was used to test the behavioural consequences of IVC housing in male and female C57BL/6JArc mice. IVC had anxiety-like effects in the elevated plus maze, which were more pronounced in female mice whereas cognition and locomotion of all test mice were not modified by IVC housing. Mice raised in IVC cage systems were socially more active than mice of filter-top systems. Furthermore, males raised in IVC exhibited an increased sensitivity to the locomotor-stimulating effects of acute MK-801 treatment compared to males in conventional cages. In summary, this is the first study revealing the longer-term effects of IVC housing on social behaviours and the locomotor response to an acute MK-801 challenge. In conclusion, researchers upgrading their holding facilities to IVC housing may encounter a shift in experimental outcomes (e.g. post pharmacological challenges) and the behavioural phenotype of test mice. Furthermore, differences between the housing conditions of breeding facilities and test facilities must carefully be considered. Finally, researchers should clarify in detail the type of housing test animals have been exposed to when publishing experimental animal research data