Early life stress is associated with greater negative emotionality and peripheral inflammation in alcohol use disorder.

Early life stress (ELS) increases risk for psychiatric illness, including alcohol use disorder (AUD). Researchers have hypothesized that individuals with and without a history of ELS who have the same primary DSM-5 diagnosis are clinically and biologically distinct. While there is strong support for this hypothesis in the context of mood disorders, the hypothesis remains largely untested in the context of AUD. This study investigated the impact of ELS on the neuroclinical phenomenology and inflammatory profile of individuals with AUD. Treatment-seeking adults with AUD (N = 163) completed the Adverse Childhood Experiences (ACE) Questionnaire and phenotypic battery as part of a pharmacotherapy trial for AUD (NCT03594435). Participants were classified as having "no-ELS," (ACE = 0) "moderate-ELS," (ACE = 1, 2 or 3) or "high-ELS" (ACE = 4 + ). The Addictions Neuroclinical Assessment domains incentive salience and negative emotionality were derived and used to assess the neuroclinical phenomenology of AUD. We tested (1) cumulative ELS as a predictor of ANA domains and (2) ELS group differences in ANA domains. A subset of participants (N = 98) provided blood samples for a biomarker of peripheral inflammation (C-reactive protein; CRP); analyses were repeated with CRP as the outcome variable. Greater ELS predicted higher negative emotionality and elevated CRP, but not incentive salience. The high-ELS group exhibited greater negative emotionality compared with the no-ELS and moderate-ELS groups, with no difference between the latter two groups. The high-ELS group exhibited elevated CRP compared with the no/moderate-ELS group. Findings suggest that high-ELS exposure is associated with a unique AUD neuroclinical presentation marked by greater negative emotionality, and inflammatory profile characterized by elevated peripheral CRP.

Leveraging meta-regression to test if medication effects on cue-induced craving are associated with clinical efficacy.

RATIONALE: The alcohol cue exposure paradigm is a common method for evaluating new treatments for alcohol use disorder (AUD); however, it is unclear if medication-related reductions in cue-induced craving in the human laboratory can predict the clinical success of those medications in reducing alcohol consumption during clinical trials. OBJECTIVES: To use a novel meta-analytic approach to test whether medication effect sizes on cue-induced alcohol craving are associated with clinical efficacy in clinical trials. METHOD: We searched the literature for medications tested for AUD treatment using both the alcohol cue-reactivity paradigm and randomized clinical trials (RCTs). For alcohol cue-reactivity studies, we computed medication effect sizes for cue-induced alcohol craving (k = 36 studies, 15 medications). For RCTs, we calculated medication effect sizes for heavy drinking and abstinence (k = 139 studies, 19 medications). Using medication as the unit of analysis, we applied the Williamson-York bivariate weighted least squares estimation to account for errors in both independent and dependent variables. We also conducted leave-one-out cross validation simulations to examine the predictive utility of cue-craving medication effect sizes on RCT heavy drinking and abstinence endpoints. RESULTS: There was no significant relationship between medication effects on cue-induced alcohol craving in the human laboratory and medication effects on heavy drinking ( ß ^ = 0.253, SE = 0.189, p = 0.090) and abstinence ( ß ^ = 0.829, SE = 0.747, p = 0.133) in RCTs. CONCLUSIONS: The preliminary results of the current study challenge the assumption that alcohol cue-reactivity alone can be used as an early efficacy indicator for AUD pharmacotherapy development. These findings suggest that a wider range of early efficacy indicators and experimental paradigms be considered for Phase II testing of novel compounds.

Neural correlates of the addictions neuroclinical assessment (ANA) incentive salience factor among individuals with alcohol use disorder.

The Addictions Neuroclinical Assessment (ANA) is a recently-developed framework offering a more holistic understanding of three neurofunctional and behavioral domains that reflect the neurobiological dysfunction seen in alcohol use disorder (AUD). While the ANA domains have been well-validated across independent laboratories, there is a critical need to identify neural markers that subserve the proposed neurofunctional domains. The current study involves secondary data analysis of a two-week experimental medication trial of ibudilast (50 mg BID). Forty-five non-treatment-seeking participants with AUD (17F / 28 M) completed a battery of validated behavioral assessments forming the basis of their incentive salience factor score, computed via factor analysis, as well as a functional neuroimaging (fMRI) task assessing their neural reactivity to visual alcohol cues after being on placebo or ibudilast for 7 days. General linear models were conducted to examine the relationship between incentive salience and neural alcohol cue-reactivity in the ventral and dorsal stratum. Whole-brain generalized linear model analyses were conducted to examine associations between neural alcohol cue-reactivity and incentive salience. Age, sex, medication, and smoking status were included as covariates. Incentive salience was not associated with cue-elicited activation in the dorsal or ventral striatum. Incentive salience was significantly positively correlated (p < 0.05) with alcohol cue-elicited brain activation in reward-learning and affective regions including the insula and posterior cingulate cortices, bilateral precuneus, and bilateral precentral gyri. The ANA incentive salience factor is reflected in brain circuitry important for reward learning and emotion processing. Identifying a sub-phenotype of AUD characterized by increased incentive salience to alcohol cues allows for precision medicine approaches, i.e. treatments specifically targeting craving and reward from alcohol use. This study serves as a preliminary bio-behavioral validation for the incentive salience factor of the ANA. Further studies validating the neural correlates of other ANA factors, as well as replication in larger samples, appear warranted.

A practice quit model to test early efficacy of medications for alcohol use disorder in a randomized clinical trial.

RATIONALE: Screening novel medications for alcohol use disorder (AUD) requires models that are both efficient and ecologically-valid. Ideally, such models would be associated with the outcomes of a given medication in clinical trials. OBJECTIVES: To test a novel human laboratory model in which individuals with intrinsic motivation to change their drinking engage in a "practice quit" attempt consisting of 6 days of complete abstinence from alcohol. METHOD: Individuals with current AUD completed a randomized, double-blind, placebo-controlled study of naltrexone (50 mg), varenicline (2 mg bid), or matched placebo. Participants were titrated onto the study medication for 1 week prior to starting the 6-day practice quit attempt. During the practice quit attempt, participants completed daily interviews with research staff. All participants completed an alcohol cue-exposure paradigm before starting the study medication and after 2 weeks of study medication. RESULTS: There were no significant medication effect on drinks per drinking day (F(2,49) = 0.66, p = 0.52) or percent days abstinent (F(2,49) = 0.14, p = 0.87) during the 6-day practice quit period. There were no medication effects on alcohol cue-reactivity (F(2,44) = 0.80, p = 0.46). Notably, participants sharply reduced their drinking during the entire 13-day medication treatment period, as compared to reducing only during the 6-day practice quit period. During the total medication period, higher levels of motivation to change was associated with higher percent days abstinent (F(1,49) = 8.12, p < 0.01). CONCLUSIONS: This study reports mostly null findings, which challenges us to decompose its nuanced design to consider model refinements. Possible changes to the model include considering the requirement for intrinsic motivation for change, including a longer practice quit period, encompassing the medication administration timeframe in the practice quit period, increasing the required sample size for signal detection, and examining a post COVID-19 pandemic cohort.

Are medication effects on subjective response to alcohol and cue-induced craving associated? A meta regression study.

RATIONALE: Alcohol administration and cue-reactivity paradigms are frequently used to screen for the initial efficacy of medications for alcohol use disorder (AUD). While medication effects on the primary outcomes for these paradigms are assumed to be qualitatively related, there is a critical lack of quantitative evidence to support this hypothesis. OBJECTIVES: The study aims to test the relationship between medication effect sizes on subjective response to alcohol administration and medication effect sizes for cue-induced craving to cue exposure, using meta-analysis. METHODS: Systematic literature searches were conducted to identify randomized trials, wherein AUD medications were tested using the alcohol administration and/or cue-reactivity paradigms. From these studies, descriptive statistics were collected to compute medication effect sizes on the primary outcomes for each respective paradigm. With medication as the unit of analysis, medication effect sizes in alcohol administration studies were compared with medication effect sizes in cue-reactivity studies using the Williamson-York regression which allows for meta-regression across independent samples. RESULTS: Medication effect sizes on alcohol-induced stimulation and alcohol-induced craving were not significantly associated with medication effect sizes on cue-induced alcohol craving (k stimulation = 10 medications, [Formula: see text] and k craving = 11 medications, [Formula: see text] (SE = 0.237), [Formula: see text]), respectively. Medication effect sizes on alcohol-induced sedation were significantly associated with medication effects on cue-induced craving (k = 10 medications, [Formula: see text] (SE = 0.258), [Formula: see text]), such that medications that increased alcohol-induced sedation were more likely to reduce cue-induced alcohol craving. CONCLUSIONS: With the exception of alcohol-induced sedation, there is little quantitative evidence of medication effects on subjective response domains measured during alcohol administration parallel medication effects on cue-induced alcohol craving. To provide additional context to the current study, future work should examine whether cue-reactivity findings predict clinical trial outcomes.

Testing pharmacotherapies for alcohol use disorder with cue exposure paradigms: A systematic review and quantitative synthesis of human laboratory trial methodology.

Alcohol cue exposure is a widely used experimental paradigm for screening pharmacotherapies for alcohol use disorder (AUD). Medication-related reductions in cue-reactivity signal early efficacy and inform medications development. Yet, across trials, the design of cue exposure, parameter testing, and outcome reporting is heterogeneous. This systematic review is a quantitative synthesis of trial methodologies and effect size estimation for AUD medication-related craving and psychophysiological outcomes under the cue exposure paradigm. A PubMed search was conducted on January 3, 2022 based on identified pharmacotherapies for peer-reviewed articles reported in English. Study-level characteristics, including sample descriptors, paradigm design, analytic approach, and Cochrane Risk of Bias, along with descriptive statistics for cue-exposure outcomes, were coded by two independent raters. Study-level effect sizes were estimated for craving and psychophysiological outcomes separately and sample-level effect sizes were calculated for each medication. Thirty-six trials, comprising 1640 participants and testing 19 different medications satisfied eligibility criteria. All studies reported on biological sex (71% male participants on average). The exposure paradigms implemented used in vivo (n = 26), visual (n = 8), and audio script (n = 2) cues. Some trials included means for craving by medication condition in text (k = 7) or figures (k = 18). The quantitative synthesis included 63 effect sizes (craving kes = 47; psychophysiological kes = 16) from 28 unique randomized trials testing 15 medications for effects on cue reactivity. For cue-induced craving, eight medications (kes range: 1-12) demonstrated small-to-medium effects (Cohen's d range: |0.24-0.64|) compared to placebo, with individuals randomized to receive medication reporting lower craving following cue exposure. Recommendations are provided to promote further consilience, so that the utility of cue exposure paradigms can be maximized in the development of effective AUD pharmacotherapies. Future work should explore the predictive utility of medication-related reductions in cue-reactivity on clinical outcomes.

Paternal alcohol exposure attenuates maintenance and reinstated operant responding for alcohol in the offspring of rats.

BACKGROUND: The heritability of alcohol use disorder is close to 50%, yet common genetic variants account for less than 5% of risk. The missing heritability may reflect environmental exposure in the parents prior to conception. Indeed, paternal alcohol exposure has many behavioral and biological consequences for rodent offspring. We recently found that paternal alcohol exposure attenuated the acquisition of operant alcohol self-administration in offspring of rats of both sexes. Here we test whether this effect extends to other phases of operant self-administration thought to model motivation, craving, and relapse. METHODS: Wistar male rats exposed to alcohol vapors or air for 6 weeks were mated with alcohol-naïve females 8 weeks later. The adult offspring were trained to lever press for alcohol and tested under several conditions: (1) maintenance responding under a progressive ratio schedule, (2) extinction responding due to removal of the alcohol delivery contingency, (3) reinstatement of extinguished responding in the presence of alcohol-associated cues, and (4) reinitiation of lever press responding for alcohol delivery under fixed and progressive ratio schedules. RESULTS: Alcohol-sired offspring showed reduced responding under the progressive ratio schedule and blunted cue-induced reinstatement of extinguished responding. Alcohol-sired offspring also emitted fewer responses during extinction sessions and did not reinitiate responding to the same extent as control-sired rats after alcohol delivery was restored. CONCLUSIONS: Across all conditions, paternal alcohol exposure led to a reduction in the reinforcing effects of alcohol in offspring. These results are consistent with studies conducted with paternal cocaine exposure except that here we find effects in rats of both sexes.

Translational models of addiction phenotypes to advance addiction pharmacotherapy.

Alcohol and substance use disorders are heterogeneous conditions with limited effective treatment options. While there have been prior attempts to classify addiction subtypes, they have not been translated into clinical practice. In an effort to better understand heterogeneity in psychiatric disorders, the National Institute for Mental Health Research Domain Criteria (RDoC) has challenged scientists to think beyond diagnostic symptoms and to consider the underlying features of psychopathology from a neuroscience-based framework. The field of addiction has grappled with this approach by considering several key constructs with the potential to capture RDoC domains. This critical review will focus on the efforts to apply translational models of addiction phenomenology in human clinical samples, including their relative strengths and weaknesses. Opportunities for forward and reverse translation are also discussed. Deep behavioral phenotyping using neuroscience-informed batteries shows promise for a better understanding of the clinical neuroscience of addiction and advancing precision medicine for alcohol and substance use disorders.

Combination treatment with varenicline and naltrexone reduces World Health Organization risk drinking levels.

BACKGROUND: The U.S. Food and Drug Administration identifies abstinence and the absence of heavy drinking days as outcomes for pharmacotherapy trials for alcohol use disorder (AUD). However, many individuals with AUD struggle to achieve these outcomes, which may discourage them from seeking treatment. World Health Organization (WHO) risk drinking levels have garnered attention in the alcohol field as potential non-abstinent outcomes for AUD medication trials. Further, testing combination pharmacotherapy for AUD represents an important direction in the field, particularly using medications such as naltrexone and varenicline, which are approved for treating AUD and smoking, respectively. The objective of the current study was to test the utility of the WHO risk drinking levels as a drinking outcome in a randomized clinical trial of combined varenicline and naltrexone for smoking cessation and drinking reduction. These analyses provide additional tests of the efficacy of this combination treatment. METHODS: The current study is a secondary analysis of a phase 2, randomized, double-blind clinical trial, wherein participants (N = 165) who were daily smokers and heavy drinkers were randomly assigned to receive either 2 mg/day of varenicline plus 50 mg/day of naltrexone or 2 mg/day of varenicline plus placebo for 12 weeks. Medication effects on 1- and 2-level reductions in WHO risk drinking levels were assessed at 4, 8, and 12 weeks into the active medication period. RESULTS: In logistic growth curve models individuals receiving the combined treatment had greater reductions in WHO risk drinking levels than individuals taking varenicline alone when assessed at 4 weeks into the active medication period. Among individuals who were WHO high and very high risk drinkers at baseline, the largest effect sizes favoring combination treatment were at Week 4 for the WHO 2-level reduction outcome (Cohen's h = 0.202) and Week 12 for the WHO 1-level reduction outcome (Cohen's h = 0.244), although these effects did not reach statistical significance. CONCLUSIONS: These findings provide evidence that combined varenicline plus naltrexone treatment is effective at reducing WHO risk drinking levels, particularly among individuals who smoke cigarettes daily and drink heavily. These results add to a growing body of literature validating reductions in WHO risk drinking levels as outcomes of alcohol medication trials.

Paternal alcohol exposure has task- and sex-dependent behavioral effect in offspring.

BACKGROUND: Endophenotypes for alcohol use disorder are well known and may reflect paternal exposure effects passed down to offspring via epigenetic mechanisms. Previously, we showed that paternal alcohol exposure prior to conception attenuates the acquisition of operant alcohol self-administration. We now test whether paternal alcohol exposure alters their offsprings' behavioral responses to alcohol (endophenotypes) and global DNA methylation levels in reward-related brain regions. METHODS: Adult male rats were exposed to alcohol vapors or air for 6 weeks and mated with alcohol-naïve females 8 weeks later. Adult male and female offspring of the alcohol- and control-sired litters were tested on three behaviors 30 m after gavage with water or alcohol (1.5 g/kg): open field, elevated plus maze, and accelerating rotarod. Global DNA methylation levels in sperm, nucleus accumbens, and prefrontal cortex were examined in male sires and in another group of offspring. RESULTS: Alcohol-sired males showed less anxiety-like behavior in the elevated plus maze that was not affected by alcohol administration. By contrast, alcohol had anxiolytic effects in the open field in male offspring only with no paternal alcohol effect. Neither paternal alcohol exposure nor alcohol administration altered locomotor activity in either sex. Sex-specific effects of paternal alcohol exposure were seen in the rotarod test. Alcohol-sired male offspring showed blunted sensitivity to the alcohol's motor-impairing effects, whereas alcohol-sired female offspring showed enhanced sensitivity. Global DNA methylation was altered in the sperm of alcohol-exposed males, but no changes were seen in their offspring. CONCLUSIONS: Paternal alcohol exposure prior to conception has sex- and task-dependent effects on unconditioned behaviors in their offspring.

Pain Catastrophizing Is Associated With Increased Alcohol Cue-Elicited Neural Activity Among Individuals With Alcohol Use Disorder.

AIMS: The current study examined the association between pain catastrophizing and alcohol cue-elicited brain activation in individuals with alcohol use disorder (AUD). METHODS: Non-treatment seeking heavy drinkers with AUD (n = 45; 28 males) completed self-report measures of pain catastrophizing and alcohol use/problems as part of a clinical trial of the neuroimmune modulator ibudilast. Participants were randomized to either placebo (n = 25) or ibudilast (n = 20) and completed an functional magnetic resonance imaging (fMRI) scan to assess neural activation to alcohol cues 1 week into the medication trial. Multiple linear regression examined whether pain catastrophizing predicted cue-induced activation in a priori regions of interest, namely the dorsal and ventral striatum (VS). An exploratory whole-brain analysis was conducted to assess the relationship between pain catastrophizing and neural alcohol cue reactivity. RESULTS: Pain catastrophizing predicted greater cue-induced activation in the dorsal (b = 0.006; P = 0.03) but not VS controlling for medication. Pain catastrophizing was positively associated with neural activation to alcohol cues in regions including the bilateral thalamus, left precuneus and left frontal pole. CONCLUSION: Greater pain catastrophizing is associated with greater cue-induced neural activation in brain regions sub-serving habits and compulsive alcohol use. These findings provide initial support for a neural mechanism by which pain catastrophizing may drive alcohol craving among individuals with AUD.

Effects of ibudilast on central and peripheral markers of inflammation in alcohol use disorder: A randomized clinical trial.

Ibudilast, a neuroimmune modulator, shows promise as a pharmacotherapy for alcohol use disorder (AUD). In vivo administration of ibudilast reduces the expression of pro-inflammatory cytokines in animal models, but its effects on markers of inflammation in humans are unknown. This preliminary study examined the effect of ibudilast on peripheral and potential central markers of inflammation in individuals with AUD. This study also explored the predictive relationship of neurometabolite markers with subsequent drinking in the trial. Non-treatment-seeking individuals with an AUD (n = 52) were randomized to receive oral ibudilast (n = 24) or placebo (n = 28) for 2 weeks. Plasma levels of peripheral inflammatory markers were measured at baseline and after 1 and 2 weeks of medication. At study mid-point, proton magnetic resonance spectroscopy was performed to measure potential neurometabolite markers of inflammation: choline-compounds (Cho), myo-inositol (MI) and creatine + phosphocreatine (Cr) in frontal and cingulate cortices from 43 participants (ibudilast: n = 20; placebo: n = 23). The treatment groups were compared on peripheral and central markers. Ibudilast-treated participants had lower Cho in superior frontal white matter and nominally lower MI in pregenual anterior cingulate cortex. Ibudilast-treated participants had nominally lower C-reactive protein levels at visit 2 and nominally lower TNF-α/IL-10 ratios, relative to placebo. C-reactive protein and Cho levels were correlated, controlling for medication. Superior frontal white matter Cho predicted drinking in the following week. Micro-longitudinal ibudilast treatment may induce peripheral and putative central anti-inflammatory responses in patients with AUD. The neurometabolite responses may be associated with reduction in drinking, suggesting an anti-inflammatory component to the therapeutic action of ibudilast.

Cannabis use and subjective response to alcohol in the human laboratory.

BACKGROUND: Cannabis is often used in combination with alcohol; yet, whether cannabis use impacts risk factors for alcohol use disorder (AUD) remains unknown. Subjective response (SR) to alcohol represents a biobehavioral risk factor for subsequent heavy drinking and for developing AUD. Given the high prevalence of alcohol and cannabis co-use, it is plausible to hypothesize that cannabis users differ in SR to alcohol compared to non-cannabis users. The purpose of this study is to examine the influence of past-month cannabis use on subjective response to alcohol in the human laboratory. METHODS: This study culled data from multiple alcohol administration trials to test whether cannabis users, compared to non-cannabis users, differed in subjective response to alcohol, comprised of four domains: stimulation, sedation, negative affect, and craving. Non-treatment-seeking heavy drinkers (N = 168) completed a battery of self-report scales of mood and alcohol/cigarette/cannabis use and problems. All participants completed an intravenous alcohol administration session wherein SR domains were measured at the following breath alcohol concentrations (BrAC): baseline (i.e., 0), 20, 40, and 60 mg%. RESULTS: Multilevel statistical analyses revealed that cannabis users had a greater reduction in negative affect during alcohol administration, compared to non-cannabis users. No significant differences were found for the other SR domains. CONCLUSIONS: Using a large sample and advanced data analytic methods, this study extends the literature by suggesting that cannabis users are more sensitive to alcohol-induced reductions in negative affect compared to non-cannabis users. This work extends research on how cannabis use may influence risk factors for AUD, such as subjective response to alcohol.

Applying the Addictions Neuroclinical Assessment to derive neurofunctional domains in individuals who use methamphetamine.

The Addictions Neuroclinical Assessment (ANA) was proposed as a neuroscience-informed clinical framework to understand heterogeneity in addiction encompassing dysfunction in three domains: incentive salience, negative emotionality, and executive functions. The ANA has been validated in the alcohol field but has not been extended to other substances. Thus, the objective of the current study was to replicate and extend the ANA framework to methamphetamine use disorder. Non-treatment seeking individuals (N = 185) who reported regular methamphetamine use completed a deep phenotyping battery comprising self-report and behavioral measures that assessed methamphetamine craving and emotional withdrawal symptoms, mood and anxiety symptomatology, risk-taking behaviors, working memory, attention, and impulsivity. Factor analytic techniques were used in an iterative manner to derive latent factors that explained biobehavioral variation in the sample. The relationship between factor scores and demographic and clinical indicators of methamphetamine use were examined to assess the construct validity of the latent factors. Deep phenotyping combined with factor analytic techniques implicated three intercorrelated neurofunctional domains that map on to the proposed ANA domains: incentive salience, negative emotionality, and executive function. Each of the domains were associated with demographic and clinical indicators of methamphetamine use providing initial support for their construct validity. The ANA framework holds promise for explaining heterogeneity in addiction by identifying neuroscience-informed phenotypes. Knowledge from the ANA framework may be applied to advance precision medicine and inform medications development for a host of substance use disorders, particularly those with no approved pharmacotherapy such as methamphetamine.

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder.

Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.

Moderators of subjective response to alcohol in the human laboratory.

BACKGROUND: Subjective response (SR) to alcohol represents a biobehavioral risk factor for heavy drinking and for developing alcohol use disorder (AUD). Identifying moderators of SR have been hindered by small sample sizes that are often used in alcohol administration studies. METHODS: This study combined data from multiple alcohol administration trials to test whether sex, family history of alcohol problems, and impulsivity (via delay discounting) predict SR to alcohol, comprised of four domains: stimulation, sedation, negative affect, and craving. Non-treatment-seeking heavy drinkers (N = 250) completed a battery of self-report scales and behavioral measures of alcohol use and problems, mood, and impulsivity. All participants completed an intravenous alcohol administration session wherein SR domains were measured at baseline, 20, 40, and 60 mg%. RESULTS: Analyses using multilevel modeling showed that male sex independently predicted higher alcohol-induced stimulation and alcohol craving, after controlling for other moderators. A family history of alcohol problems also independently predicted alcohol craving after controlling for other moderators. CONCLUSIONS: Using a large sample and advanced data analytic methods, this study extends the literature on alcohol administration by identifying important moderators of SR in heavy drinkers: namely, male sex and family history of alcohol problems. These findings consolidate and extend a growing body of research aimed at differentiating individuals most likely to report the SR features that confer risk for AUD.

Additive roles of tobacco and cannabis co-use in relation to delay discounting in a sample of heavy drinkers.

RATIONALE: Alcohol use disorder (AUD) is associated with steeper delay discounting rates; however, it is unknown whether substance co-use, particularly cannabis use, has an additive effect on discounting rates among heavy drinkers. Furthermore, it is unclear whether substance co-use and delay discounting are independently associated with AUD severity. OBJECTIVES: The purpose of this study was to determine whether alcohol, tobacco, and cannabis co-use impacts delay discounting rates. We also sought to determine whether substance co-use and delay discounting were associated with AUD symptom counts. METHODS: The study sample was culled from several human laboratory studies and consisted of 483 heavy drinking individuals who completed a baseline visit (prior to experimental procedures). Participants were divided into groups based on self-reported alcohol, tobacco, and cannabis use during the past 30 days: alcohol only (n = 184), alcohol + cigarettes (n = 89), alcohol + cannabis (n = 82), and tri-use (n = 128). We examined discounting rates across the 4 groups and used multiple linear regression to test whether co-use and delay discounting were associated with AUD symptoms. RESULTS: After adjusting for covariates, individuals in the alcohol + cannabis group and the tri-use group had steeper discounting rates relative to the alcohol-only group. In addition, tri-use and delay discounting rates were independently correlated with a greater number of AUD symptoms. CONCLUSIONS: Delay discounting rates were significantly greater among subgroups reporting cannabis use providing partial support for an additive effect, while also highlighting the importance of co-use substance type. Both tri-use and delay discounting were associated with greater AUD severity, which may provide relevant intervention targets.

Paternal alcohol exposure reduces acquisition of operant alcohol self-administration and affects Bdnf DNA methylation in male and female offspring.

Familial transmission of alcohol use disorder reflects genetic and environmental factors. Paternal alcohol exposure may affect rodent offspring via epigenetic modifications transmitted through the male germ line. While such exposure alters alcohol sensitivity in mouse offspring, no studies examined if it impacts the development of operant alcohol self-administration in rats. We exposed male (sires) Wistar rats to chronic intermittent ethanol in vapour chambers (16 h/day; 5 days/week) or to air for 6 weeks. Eight weeks later, rats were mated with alcohol-naive females. Adult alcohol- and control-sired F1 offspring were assessed in acquisition of alcohol self-administration in which increasing alcohol concentrations (2.5%, 5% and 10%, v/v) were delivered after one lever press (fixed ratio 1 or FR1). Prior to alcohol sessions, rats were trained to lever press for food delivery under an FR1 schedule of reinforcement. DNA methylation levels of the brain derived neurotrophic factor (Bdnf) gene were measured in sperm, nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) in sires and in offspring. Alcohol-exposed sires had lower Bdnf DNA methylation levels in NAc and greater methylation levels in mPFC. Although this pattern was not recapitulated in offspring, alcohol-sired offspring of both sexes did show aberrant Bdnf DNA methylation patterns compared to control-sired offspring. Alcohol-sired offspring self-administered less alcohol (5% and 10%) with no group differences in food responding. Results indicate that paternal alcohol exposure prior to conception protects against alcohol's initial reinforcing effects but the pattern of dysregulated Bdnf methylation in reward-related circuitry did not mimic changes seen in sires.

Translational opportunities in animal and human models to study alcohol use disorder.

Animal and human laboratory paradigms offer invaluable approaches to study the complex etiologies and mechanisms of alcohol use disorder (AUD). We contend that human laboratory models provide a "bridge" between preclinical and clinical studies of AUD by allowing for well-controlled experimental manipulations in humans with AUD. As such, examining the consilience between experimental models in animals and humans in the laboratory provides unique opportunities to refine the translational utility of such models. The overall goal of the present review is to provide a systematic description and contrast of commonly used animal paradigms for the study of AUD, as well as their human laboratory analogs if applicable. While there is a wide breadth of animal species in AUD research, the paradigms discussed in this review rely predominately on rodent research. The overarching goal of this effort is to provide critical analysis of these animal models and to link them to human laboratory models of AUD. By systematically contrasting preclinical and controlled human laboratory models, we seek to identify opportunities to enhance their translational value through forward and reverse translation. We provide future directions to reconcile differences between animal and human work and to improve translational research for AUD.

Immune receptor toll-like receptor 4 contributes to stress-induced affective responses in a sex-specific manner.

Stress activates innate immune Toll-like receptors (TLRs) and enhances susceptibility to depression, a condition that is more prevalent in females. The TLR4 receptor type is involved in inflammatory responses and its expression levels associate with depressive symptoms and their successful treatment. Yet, little preclinical research has examined the role of TLR4 in stress-induced affective responses to determine if these are sex-specific. One group per genotype of male and female Tlr4 knockout (KO) and wild type (WT) rats were exposed to predator odor in a place conditioning apparatus with others exposed to saline. Affective behaviors evaluated included distance traveled and center time in an open-field apparatus, sucrose preference and fluid intake in a two-bottle test, and conditioned place aversion to the odor-paired compartment. Predator odor exposed rats showed conditioned place aversion to the odor-paired compartment, demonstrating predator odor was aversive. Such exposure led to anhedonia (decreased sucrose preference) across genotypes and sex. Predator odor exposure decreased distance traveled, an effect that was greater in KO rats, especially in females. Tlr4 deletion also resulted in sex-specific effects on anxiety-like behavior. Compared to WTs, female KO rats showed lower center time after predator odor exposure whereas genotype did not affect this response in male rats. Across litters, fewer male KO and heterozygous rats and more WT rats were born whereas female rats showed the typical genotype distribution. Results suggest predator odor alters affective behaviors, consistent with the preclinical literature, and deletion of Tlr4 enhances some stress-induced affective responses, often in a sex-specific manner.