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.

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.

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.

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.

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.

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.

A meta-regression of methodological features that predict the effects of medications on the subjective response to alcohol.

BACKGROUND: Alcohol administration paradigms have been used for early efficacy testing of novel compounds for alcohol use disorder (AUD). There has been an ongoing debate about sample characteristics and methodological features that affect the likelihood of detecting an early efficacy signal for AUD medications. We conducted a meta-regression to test whether the drinking level of the study sample and the peak breath alcohol concentration (BrAC) in the alcohol administration study predict the efficacy of AUD pharmacotherapies on the subjective responses to alcohol. METHODS: We computed the effects of 21 medications on alcohol-induced stimulation, sedation, negative mood, and craving during alcohol administration in 49 studies. RESULTS: Meta-regression analyses indicated a significant and positive effect of pre-study drinks per month on alcohol-induced stimulation (ß = 0.142, p < 0.0001), such that as drinking increases, the benefit of medication over placebo decreases. There was an effect of drinks per month on negative mood (ß = -0.164, p = 0.0248), such that at higher levels of drinks per month, the effects of medications on negative mood are stronger. For sedation, there was an effect of peak BrAC (ß = 0.119, p = 0.0002), such that at low levels of peak BrAC, the effects of medication on sedation were null. For craving, there was a peak BrAC × drinks per month interaction such that at low levels of BrAC, a heavier drinking sample is required to detect the effects of medication on craving. Sensitivity analyses comparing naltrexone studies and non-naltrexone studies suggested that naltrexone was less sensitive to drinks per month across subjective response domains. CONCLUSIONS: These analyses show that design features are critical in studies that test the effects of medications on the subjective responses to alcohol. By specifying the significance and directionality of these effects, as well as the specific points in BrAC or drinks per month at which medication effects are detectable, the study offers recommendations for design features of alcohol administration studies that aim to inform AUD medication development.

Baseline Drinking Patterns in Non-Treatment Seeking Problem Drinkers.

AIMS: Natural processes of change have been documented in treatment-seekers who begin to reduce their drinking in anticipation of treatment. The study examined whether non-treatment-seeking problem drinkers would engage in drinking reduction in anticipation of participating in a research study. METHODS: Non-treatment-seeking problem drinkers (n = 935) were culled from five behavioral pharmacology studies. Participants reported on their alcohol use during the past 30 days using the Timeline Followback. Cluster analysis identified distinct groups/clusters based on drinking patterns over the 30-day pre-visit period. The identified clusters were compared on demographic and clinical measures. RESULTS: Three distinct clusters were identified (a) heavy-decreasing drinking group (n = 255, 27.27%); (b) a moderate-stable drinking group (n = 353, 37.75%) and (c) low-stable drinking group (n = 327, 34.97%). The three clusters differed significantly on a host of measures including pre-visit drinking (age at first drink, drinking days, drinks per week, drinks per drinking day), alcohol use severity, alcohol craving, readiness for change, depression and anxiety levels. These differences were alcohol dose-dependent such that the heavier drinking group reported the highest levels on all constructs, followed by the moderate group, and the low drinking group last. CONCLUSIONS: Baseline drinking patterns of non-treatment-seekers were generally stable and pre-visit reductions were only observed among the heavy drinking group. This generally stable pattern stands in contrast to previous reports for treatment-seeking samples. Nevertheless, the heavier drinking group, which is most similar to treatment-seekers, displayed pre-study drinking reduction. Overall, naturalistic processes of change may pose less of a threat to randomization and testing in this population.

Persistence of Operant Responding for Food After Prior Cocaine Exposure in Fischer 344 But Not Lewis Rats.

BACKGROUND AND OBJECTIVES: Chronic cocaine exposure has differential neural effects in Fischer 344 (F344) vs Lewis inbred rats that may explain strain-dependent differences during acquisition vs maintenance of cocaine self-administration. We assessed whether prior cocaine exposure alters operant responding for food across various phases (acquisition, maintenance, extinction, spontaneous recovery, reinitiation) in these strains. METHODS: Lewis and F344 rats (N = 12) were administered three cocaine (15 mg/kg) or saline injections at hourly intervals for 3 consecutive days. Beginning the next day for 24 days, rats had access to operant chambers in which one lever depression resulted in the delivery of a food pellet. Then, four extinction sessions were conducted in which food was no longer available, but other stimulus conditions remained the same. After a 2-day break, spontaneous recovery was assessed over four sessions. Food delivery was then restored for 3 days to test reinitiation followed by a progressive ratio session. RESULTS: Lewis rats acquired the operant faster than F344 rats. F344 rats showed lower maintenance rates than Lewis rats but higher spontaneous recovery responding. Cocaine exposure caused persistence of responding during extinction in F344 but not Lewis rats. All groups reinitiated responding when food was available again and did not differ in final ratios completed under the progressive ratio schedule. DISCUSSION AND CONCLUSIONS: That prior cocaine exposure led to persistence of responding in F344 rats during extinction may reflect heightened contextual conditioning that interferes with the ability to extinguish responding. SCIENTIFIC SIGNIFICANCE: Results have implications for the genetic contribution to relapse-like behaviors. (Am J Addict 2021;00:00-00).

Lifetime heavy drinking years predict alcohol use disorder severity over and above current alcohol use.

Background: Preclinical studies demonstrate that chronic and heavy alcohol use facilitates neuroadaptations that perpetuate addiction-like behaviors. In clinical studies, it is unclear whether the extent of heavy alcohol use over the lifetime contributes to alcohol use disorder (AUD) severity over and above current alcohol use patterns (i.e. last 30 days to 3-months). Such information may improve our understanding of the phenomenology of AUD.Objectives: The purpose of this study was to examine lifetime heavy drinking years in relation to a clinical assessment of AUD.Methods: Participants, who were non-treatment-seeking and engaged in heavy drinking (n = 140; 50% male), completed an interview-based assessment of lifetime regular and heavy drinking years along with a battery of measures indexing alcohol use and problems, drinking motives, and depression and anxiety symptomatology.Results: Lifetime heavy drinking years was positively associated with lifetime regular drinking years, current alcohol use, alcohol problems, tonic alcohol craving, drinking for the enhancing effects of alcohol, and drinking to cope (r's = .21-.58). Adjusting for lifetime regular drinking years and current alcohol use, lifetime heavy drinking years predicted higher scores on the Alcohol Use Disorder Identification Test (AUDIT; B = .382; SE = .123). A multivariate logistic regression found that lifetime heavy drinking years predicted greater odds of more severe AUD over and above current alcohol use (OR = 1.147).Conclusion: Our findings suggest that lifetime heavy drinking years are a clinically meaningful indicator of AUD severity that is not redundant with current alcohol use measures.

Intravenous Alcohol Administration Selectively Decreases Rate of Change in Elasticity of Demand in Individuals With Alcohol Use Disorder.

BACKGROUND: Alcohol demand is a key behavioral economic concept that provides an index of alcohol's relative reinforcing value. Initial studies have reported that alcohol demand increases during alcohol administration and in response to alcohol cues. However, the extent to which these effects are observed explicitly in samples composed of individuals with alcohol use disorder (AUD) and are operative in conjunction with each other has not been studied. METHODS: To address this gap in the literature, we assessed alcohol demand during an alcohol challenge and subsequent alcohol cue-exposure paradigm in non-treatment-seeking, alcohol-dependent (i.e., DSM-IV criteria) participants (N = 27). Specifically, participants completed 2 counterbalanced intravenous, placebo-controlled, alcohol administration sessions followed by a controlled cue-exposure paradigm. At baseline and at breath alcohol concentration of 0.06 g/dl, participants completed the alcohol purchase task, assessing estimated alcohol consumption at escalating prices. Participants were also assessed for alcohol demand following each cue exposure. RESULTS: During alcohol administration, there was a significant decrease in the rate of change in elasticity compared with placebo, and during the cue-reactivity paradigm, there was a significant main effect such that alcohol cues decreased the rate of change in elasticity relative to water cues. There were no statistically significant differences in other demand indices. CONCLUSIONS: These findings provide further evidence that alcohol administration increases price insensitivity and extends the literature on alcohol's effects on demand by using a clinical sample with AUD and by adding a placebo-alcohol condition.

Reward, Relief and Habit Drinking: Initial Validation of a Brief Assessment Tool.

AIMS: Alcohol use disorder is highly heterogeneous. One approach to understanding this heterogeneity is the identification of drinker subtypes. A candidate classification consists of reward and relief subtypes. The current study examines a novel self-report measure of reward, relief, and habit drinking for its clinical correlates and subjective response (SR) to alcohol administration. METHODS: Non-treatment-seeking heavy drinkers (n = 140) completed the brief reward, relief, habit drinking scale (RRHDS). A subset of this sample (n = 67) completed an intravenous alcohol administration. Individuals were classified into drinker subtypes. A crowdsourced sample of heavy drinkers (n = 187) completed the RRHDS and a validated reward relief drinking scale to compare drinking classification results. RESULTS: The majority of the sample was classified as reward drinkers (n = 100), with fewer classified as relief (n = 19) and habit (n = 21) drinkers. Relief and habit drinkers reported greater tonic alcohol craving compared to reward drinkers. Reward drinkers endorsed drinking for enhancement, while relief drinkers endorsed drinking for coping. Regarding the alcohol administration, the groups differed in negative mood, such that relief/habit drinkers reported a decrease in negative mood during alcohol administration, compared to reward drinkers. The follow-up crowdsourcing study found a 62% agreement in reward drinker classification between measures and replicated the tonic craving findings. CONCLUSIONS: Our findings suggest that reward drinkers are dissociable from relief/habit drinkers using the brief measure. However, relief and habit drinkers were not successfully differentiated, which suggests that these constructs may overlap phenotypically. Notably, measures of dysphoric mood were better at detecting group differences than measures capturing alcohol's rewarding effects.

Fluoxetine exposure during adolescence alters responses to aversive stimuli in adulthood.

The mechanisms underlying the enduring neurobiological consequences of antidepressant exposure during adolescence are poorly understood. Here, we assessed the long-term effects of exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, during adolescence on behavioral reactivity to emotion-eliciting stimuli. We administered FLX (10 mg/kg, bi-daily, for 15 d) to male adolescent [postnatal day 35 (P35) to P49] C57BL/6 mice. Three weeks after treatment (P70), reactivity to aversive stimuli (i.e., social defeat stress, forced swimming, and elevated plus maze) was assessed. We also examined the effects of FLX on the expression of extracellular signal-regulated kinase (ERK) 1/2-related signaling within the ventral tegmental area (VTA) of adolescent mice and Sprague Dawley rats. Adolescent FLX exposure suppressed depression-like behavior, as measured by the social interaction and forced swim tests, while enhancing anxiety-like responses in the elevated plus maze in adulthood. This complex behavioral profile was accompanied by decreases in ERK2 mRNA and protein phosphorylation within the VTA, while stress alone resulted in opposite neurobiological effects. Pharmacological (U0126) inhibition, as well as virus-mediated downregulation of ERK within the VTA mimicked the antidepressant-like profile observed after juvenile FLX treatment. Conversely, overexpression of ERK2 induced a depressive-like response, regardless of FLX pre-exposure. These findings demonstrate that exposure to FLX during adolescence modulates responsiveness to emotion-eliciting stimuli in adulthood, at least partially, via long-lasting adaptations in ERK-related signaling within the VTA. Our results further delineate the role ERK plays in regulating mood-related behaviors across the lifespan.

Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice.

Abstract Exposure to stress is highly correlated with the emergence of mood-related illnesses. Because major depressive disorder often emerges in adolescence, we assessed the effects of social defeat stress on responses to depressive-like behaviors in juvenile mice. To do this, postnatal day (PD) 35 male c57BL/6 mice were exposed to 10 days of social defeat stress (PD35-44), while control mice were handled daily. Twenty-four hours after the last episode of defeat (PD45), separate groups of mice were tested in the social interaction, forced swimming, sucrose preference, and elevated plus-maze behavioral assays (n = 7-12 per group). Also, we examined body weight gain across days of social defeat and levels of blood serum corticosterone 40 min after the last episode of defeat stress. Our data indicates that defeated mice exhibited a depressive-like phenotype as inferred from increased social avoidance, increased immobility in the forced swim test, and reduced sucrose preference (a measure of anhedonia), when compared to non-defeated controls. Defeated mice also displayed an anxiogenic-like phenotype when tested on the elevated plus-maze. Lastly, stressed mice displayed lower body weight gain, along with increased blood serum corticosterone levels, when compared to non-stressed controls. Overall, we show that in adolescent male c57BL/6 mice, social defeat stress induces a depression- and anxiety-like phenotype 24 h after the last episode of stress. These data suggest that the social defeat paradigm may be used to examine the etiology of stress-induced mood-related disorders during adolescence.

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.

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.

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.

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.

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.