The medial prefrontal cortex integrates information about salience and valence of stimuli, including rewarding solutions like alcohol and sucrose, and regulates aspects of alcohol seeking and consumption. However, our understanding of how cortical outputs encode alcohol consumption is limited. Using fiber photometry to measure calcium activity in putative prelimbic (PrL) glutamatergic projection neurons, we show similar but distinct patterns of activity during the peri-consummatory phase in response to consumption of water (non-deprived conditions), ethanol (20% v/v), or sucrose (1% w/v). PrL population activity appears to track hedonic value, as GCaMP6f signals ramped immediately preceding bouts for water, ethanol, and sucrose, and the signal scaled with presumed hedonic value, i.e., water<ethanol<sucrose. Further, using machine learning, population activity of PrL neurons prior to consumption was sufficient to predict both consumption of and distinguish between these different solutions. To assess valence encoding, we adulterated the ethanol solution with quinine, a bitter tastant. In non-dependent mice, calcium activity surrounding drinking bouts was reduced, paralleling the decreased consumption of quinine-adulterated ethanol. This effect was not present in ethanol dependent mice, suggesting altered hedonic value of the adulterated solution either due to reduced sensitivity to the aversiveness of quinine or increased sensitivity to the reinforcing value of ethanol. The global population of PrL glutamatergic neurons also display sustained GCaMP6f 'up-states' that last tens to hundreds of seconds, which were longer and larger when consummatory bouts occurred. Overall, our results demonstrate a functional signature in PrL neurons that differs across solutions and is disrupted by ethanol dependence.

Background Partially due to the complexity associated with conducting trials, there have been relatively few regulatory agency-approved medications for the treatment of alcohol use disorder (AUD). Heterogeneity of study samples, such as participant characteristics (including variation in alcohol consumption) as well as drinking efficacy endpoints, may lead to inconsistency in results and a potential increase in Type II errors. The aim of this study is to begin to fill in the knowledge gap of optimal clinical trial design by analyzing potential predictors of outcomes.Methods Five federally funded and publicly available multisite randomized pharmacotherapy clinical trials for the treatment of AUD using similar methodologies to assess drinking outcomes were included. Three FDA-guided drinking efficacy outcomes were calculated for each study independently and combined: abstinence (no drinking days), no heavy drinking days, WHO 2+ risk drinking level (RDL) reduction as well as a measure of study participant completion. These outcomes were analyzed by logistic regression models including a variety of predictors within the full-study sample as well as among only participants treated with placebo.Results The number of days abstinent prior to randomization was a strong positive predictor of all three predefined drinking outcomes. Further analysis indicated a cutoff of less than three to five abstinent days before randomization might be optimal. For the WHO 2+ RDL endpoint, those within the "high" or "very-high" risk categories were more likely to meet criteria for successful two or more risk level reductions than "medium" risk. Across various demographic variables, only age (older participants) was associated with better outcomes.Conclusions These findings suggest that some important prestudy drinking characteristics (e.g., less abstinence and older age) as well as being in a higher risk drinking category should be considered for inclusion in future alcohol pharmacotherapy trials.

INTRODUCTION:There is a persistent scarcity of research examining telehealth delivery of evidence-based alcohol use disorder (AUD) interventions. This secondary analysis explored whether Alcohol Behavioral Couple Therapy (ABCT) treatment outcomes differed when delivered via telehealth versus in-person. METHOD:Participants were N = 96 adult romantic couples enrolled in a clinical trial in which all participants received ABCT. Couples who participated entirely in person (n = 15) were compared to those who completed at least one telehealth session (n = 81). We compared 1) feasibility and acceptability (e.g., number of sessions attended, participant and therapist-rated therapeutic alliance), 2) alcohol consumption, 3) alcohol problem severity, and 4) relationship adjustment among participants in the telehealth and in-person group at the end of the treatment phase. RESULTS:Identified patients (IPs) in the in-person group reported slightly stronger participant-rated therapeutic alliance scores than those in the telehealth group (113.2 vs. 105.9, p < .01). Partners in the telehealth group evidenced a substantial reduction in percent drinking days whereas partners in the in-person group evidenced a slight increase (-16.1% vs. +2.3%, p = .02). No other group differences emerged between IPs or partners. CONCLUSIONS:These findings support the feasibility, acceptability, and rigor of ABCT delivered via telehealth, which can help offset critical systemic barriers to accessing evidence-based couple therapy for AUD.

With growing knowledge of the neural circuitry involved in alcohol use disorder (AUD), interest in developing neural-circuit-based therapeutic tools, including transcranial magnetic stimulation (TMS), for people with AUD has increased. While mounting evidence supports the efficacy of TMS for AUD, multiple dosing protocols are currently under consideration, and little is known about the neurobiological mechanisms through which TMS leads to clinical improvement. This randomized, sham-controlled, double-blind, crossover study was designed to address this gap by evaluating the impact of a single session of two prominent TMS protocols (each relative to sham), 10 Hz TMS to dorsolateral prefrontal cortex (dlPFC) and continuous theta burst stimulation (cTBS) to medial PFC (mPFC), on levels of excitatory (glutamate, glutamine, glycine) and inhibitory (GABA) neurometabolites, using proton MR spectroscopy (MRS), in the tissue beneath the TMS coil in treatment-naïve individuals with AUD. Seventy men and women, aged 21-40 years, with moderate-severe AUD were enrolled into the study and randomly assigned to complete one of six experimental condition orders, each consisting of three TMS sessions (cTBS, 10 Hz TMS, sham) conducted on three separate days, each immediately followed by MRI/MRS. Whereas cTBS to mPFC was associated with relatively lower levels of excitatory neurometabolites (glutamine and glycine, with additional mixed support for glutamate), 10 Hz TMS to dlPFC was not, and neither protocol was associated with GABA levels. Together, these findings demonstrate acute neurochemical target engagement under the coil with a single session of cTBS to mPFC, pointing to the utility of assaying neurometabolites in further optimizing this and other candidate targets for AUD.

Alcohol Use Disorder (AUD) is a significant health concern characterized by cognitive dysfunction and an inability to control alcohol intake, leading to severe social and health consequences. It is crucial to uncover neuroadaptations and cellular mechanisms responsible for poor decisions surrounding alcohol drinking. Although the mediodorsal thalamus (MD) is an essential brain region for cognitive function and reward-guided choices, the effects of alcohol dependence on MD neuroadaptations and how dependence alters MD activity during choice behaviors for alcohol over natural rewards (i.e., sucrose) are not well understood. Genetic and physiological adaptations in the MD were assessed in mice treated with the chronic intermittent ethanol (CIE) exposure model of dependence, which increased alcohol intake and preference during choice sessions for water or sucrose in males and females. Results indicated that CIE exposure induced time-dependent changes in c-Fos and transcript expression and increased excitability of MD neurons during withdrawal. Enrichment analysis of alcohol-sensitive genes revealed dysregulation of genes that control glial function and axonal myelination. Fiber photometry recordings demonstrated that MD activity was elevated at the start of and after licking bouts for alcohol, water, or sucrose, and the signal for alcohol was significantly higher than the signal for other solutions in control and alcohol dependent mice. These findings demonstrate that CIE exposure causes alcohol-biased choice behaviors and genetic and physiological neuroadaptations in the MD, with MD neurons showing a unique response to alcohol over other solutions.

Innovative and accessible interventions are critical to address rising rates of alcohol misuse and low rates of alcohol treatment engagement among women. Ecological momentary interventions (EMI) that use technology to deliver interventions in real-time may be a promising avenue to reduce barriers to alcohol interventions for women and ensure they receive intervention when they need it most. Craving is a key proximal predictor of alcohol use that may be beneficial to target using EMI. Tetris is a visuospatial task that may disrupt craving by placing competing demands on visual working memory. This study tested a Tetris EMI for craving and alcohol use among women who reported alcohol misuse. Forty women completed a two-week experimental EMA protocol involving a daily interval-contingent survey assessing past-day alcohol craving and consumption, as well as four daily signal-contingent surveys assessing momentary craving. Participants assigned to the intervention condition (n = 20) were prompted to complete Tetris for four minutes in response to momentary craving and those assigned to the control condition (n = 20) were prompted to wait four minutes before re-rating craving. Participants also completed baseline and post-experimental questionnaires. Results indicated that the Tetris EMI was highly acceptable and generally feasible. The EMI predicted average decreases in momentary craving for those who reported high levels of recognition of possible harms related to their drinking and readiness to change. However, the EMI did not lead to decreases in average daily craving or drinking. Findings suggest craving is a modifiable target for EMIs among women who are more ready for treatment.

Alcohol use disorder (AUD) is a chronic disease that poses significant economic burden and health risks. It is pivotal to better understand brain mechanisms engaged by alcohol that promote misuse. The central amygdala (CeA) has emerged as a key mediator of excessive alcohol consumption in preclinical models. A dynorphin-expressing subpopulation within the CeA (CeADyn) has been implicated in excessive alcohol drinking, yet how cellular activity of CeADyn neurons relates to ongoing alcohol drinking is not well-understood. The current study interrogated the engagement of CeADyn neurons in male and female mice during voluntary alcohol consumption using fiber photometry and compared this cellular response with that of other solutions having similar motivational and/or taste characteristics. Activity of a calcium sensor, GCaMP7f, expressed in mouse CeADyn neurons was recorded and time-locked to drinking bouts. Advanced fiber photometry normalization and mixed modeling methods were developed to better resolve effects, revealing relatively large increases in CeADyn neuron calcium transients after bouts of alcohol drinking compared to water or sucrose drinking. This indicates that these neurons are uniquely engaged during alcohol consumption. Alcohol-specific drinking behavior (i.e., longer bout durations) did not fully explain signal differences between alcohol and other solutions nor did the relatively increased alcohol response diminish over time. No other conditions or solutions tested reproduced the pronounced change in CeADyn activity associated with alcohol drinking. These findings support the presence of a unique functional signature for alcohol in a cell population known to control excessive alcohol drinking and further advance fiber photometric normalization and analytical methods.

Aims Among individuals with alcohol use disorder (AUD), sleep disturbances are pervasive and contribute to the etiology and maintenance of AUD. However, despite increased attention toward the relationship between alcohol use and sleep, limited empirical research has systematically examined whether reductions in drinking during treatment for AUD are associated with improvements in sleep problems.Methods We used data from a multisite, randomized, controlled trial that compared 6 months of treatment with gabapentin enacarbil extended-release with placebo for adults with moderate-to-severe AUD (N = 346). The Timeline Follow-back was used to assess WHO risk drinking level reductions and the Pittsburgh Sleep Quality Index was used to assess sleep quality over the prior month at baseline and the end of treatment.Results Sleep problem scores in the active medication and placebo groups improved equally. Fewer sleep problems were noted among individuals who achieved at least a 1-level reduction (B = -0.99, 95% confidence interval (CI) [-1.77, -0.20], P = .014) or at least a 2-level reduction (B = -0.80, 95% CI [-1.47, -0.14], P = .018) in WHO risk drinking levels at the end of treatment. Reductions in drinking, with abstainers excluded from the analysis, also predicted fewer sleep problems at the end of treatment (1-level: B = -1.01, 95% CI [-1.83, -0.20], P = .015; 2-level: B = -0.90, 95% CI [-1.59, -0.22], P = .010).Conclusions Drinking reductions, including those short of abstinence, are associated with improvements in sleep problems during treatment for AUD. Additional assessment of the causal relationships between harm-reduction approaches to AUD and improvements in sleep is warranted. Short Summary: This study investigated the relationship between reductions in alcohol consumption and sleep quality during treatment for alcohol use disorder (AUD). Findings indicated that reductions in WHO drinking risk levels, including those short of abstinence, were associated with improvements in sleep, suggesting the potential benefits of harm-reduction approaches in treating AUD.

OBJECTIVES:Alcohol consumption affects sleep both in healthy populations and in patients with alcohol use disorder (AUD). However, sleep has typically not been considered within AUD pharmacotherapy trials. We used data from a completed gabapentin clinical treatment trial to explore the medication's effect on patient-rated insomnia measured by a standard insomnia rating (Insomnia Severity Index [ISI]) and whether this influenced gabapentin's effects on alcohol consumption. METHODS:This study included 90 individuals with current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition AUD criteria reporting current or past alcohol withdrawal. Participants were assigned to placebo or gabapentin (up to 1200 mg/day) for a 16-week randomized controlled trial with percent heavy drinking days (PHDD) and percent abstinent days (PDA) as outcomes. Utilizing mixed-effects models, this study assessed medication effects on ISI over the trial. We then examined the interaction of baseline ISI and medication on drinking. Finally, given our previous finding of alcohol withdrawal influencing gabapentin efficacy, we added change in ISI as a potential "moderator" of the interaction of medication effects and alcohol withdrawal on drinking. RESULTS:Sleep (ISI) improved more in those treated with gabapentin (60.6% reduction) compared with placebo (37.8% reduction; P = 0.013). Higher baseline ISI predicted drinking in gabapentin-treated individuals (lower PHDD [ P = 0.026] and higher (PDA [ P = 0.047]). ISI was an independent predictor of PHDD decrease and PDA increase ( P < 0.001; P = 0.002), but this did not significantly moderate gabapentin's effectiveness. CONCLUSIONS:Although gabapentin positively impacts both alcohol use and sleep, its effect on drinking is not fully dependent on sleep improvement, implying a direct biological mechanism on alcohol use.

Alcohol Use Disorder (AUD) is a significant health concern characterized by an individual's inability to control alcohol intake. With alcohol misuse increasing and abstinence rates declining, leading to severe social and health consequences, it is crucial to uncover effective treatment strategies for AUD by focusing on understanding neuroadaptations and cellular mechanisms. The mediodorsal thalamus (MD) is a brain region essential for cognitive functioning and reward-guided choices. However, the effects of alcohol (ethanol) dependence on MD neuroadaptations and how dependence alters MD activity during choice behaviors for alcohol and a natural reward (sucrose) are not well understood. Adult C57BL/6J mice treated with chronic intermittent ethanol (CIE) exposure were used to assess genetic and functional adaptations in the MD. Fiber photometry-based recordings of GCaMP6f expressed in the MD of C57BL/6J mice were acquired to investigate in vivo neural adaptations during choice drinking sessions for alcohol (15%) and either water or sucrose (3%). There were time-dependent changes in cFos and transcript expression during acute withdrawal and early abstinence. Differentially expressed genes were identified in control mice across different circadian time points and when comparing control and alcohol dependent mice. Gene Ontology enrichment analysis of the alcohol-sensitive genes revealed disruption of genes that control glial function, axonal myelination, and protein binding. CIE exposure also increased evoked firing in MD cells at 72 hours of withdrawal. In alcohol-dependent male and female mice that show increased alcohol drinking and preference for alcohol over water, we observed an increase in alcohol intake and preference for alcohol when mice were given a choice between alcohol and sucrose. Fiber photometry recordings demonstrated that MD activity is elevated during and after licking bouts for alcohol, water, and sucrose, and the signal for alcohol is significantly higher than that for water or sucrose during drinking. The elevated signal during alcohol bouts persisted in alcohol dependent mice. These findings demonstrate that CIE causes genetic and functional neuroadaptations in the MD and that alcohol dependence enhances alcohol-biased behaviors, with the MD uniquely responsive to alcohol, even in dependent mice.

Background: Symptoms often play an important role in the scientific inquiry of psychological disorders and have been theorized to play a functional role in the disorders themselves. However, little is known about the course of specific symptoms and individual differences in course. Understanding the course of specific symptoms and factors influencing symptom course can inform psychological theory and future research on course and treatment.Methods: The current study examined alcohol use disorder (AUD) criteria to explore how etiologically relevant covariates differentially affected the course of individual criteria. The study examined 34,653 participants from Wave 1 (2001-2002) and Wave 2 (2003-2004) of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), to analyze the extent to which AUD symptom course is predicted by alcohol consumption patterns, family history of alcoholism, the presence of internalizing and externalizing disorders, and race.Results: The course of all AUD criteria was significantly influenced by these predictors, with the magnitude of the influence varying across different criteria and different aspects of the course (i.e., onset, persistence, recurrence). The strength of the relationship is partially related to the theoretical proximity of a given covariate to AUD symptomatology, with heavy drinking being the strongest and family history of AUD being the weakest. The course of all criteria was strongly associated with the prevalence of the criterion in the overall sample.Conclusions: The course of AUD criteria is heterogeneous, appearing to be influenced by conceptually proximal predictors, the prevalence of the criterion, and perhaps an underlying common factor. Diagnostic accuracy may be improved by including a criterion related to alcohol consumption. Future work should include exploring the interchangeability of criteria and alternative operationalization of them.

Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone's effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934.

Modern theoretical models of Alcohol Use Disorder (AUD) highlight the different functional roles played by various mechanisms associated with different symptoms. Symptom network models (SNMs) offer one approach to modeling AUD symptomatology in a way that could reflect these processes and provide important information on the progression and persistence of disorder. However, much of the research conducted using SNMs relies on cross-sectional data, which has raised questions regarding the extent they reflect dynamic processes. The current study aimed to (a) examine symptom networks of AUD and (b) compare the extent to which cross-sectional network models had similar structures and interpretations as longitudinal network models. 17,360 participants from Wave 1 (2001-2002) and Wave 2 (2003-2004) of the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) were used to model cross-sectional and longitudinal AUD symptom networks. The cross-sectional analyses demonstrate high replicability across waves and central symptoms consistent with other cross-sectional studies on addiction networks. The longitudinal network shared much less similarity than the cross-sectional networks and had a substantially different structure. Given the increasing attention given to the network perspective in psychopathology research, the results of this study raise concerns about interpreting cross-sectional symptom networks as representative of temporal changes occurring within a psychological disorder. We conclude that the psychological symptom network literature should be bolstered with additional research on longitudinal network models.

Individuals with alcohol use disorder continue to drink in excess despite the health and societal consequences, and the rate of problematic drinking and alcohol-related harms is increased in women. Clinical imaging studies report widespread adaptations in brain structure after chronic, heavy drinking, and alcohol-related cues enhance brain reactivity in reward-related regions. In rodents, alcohol drinking induces expression of the immediate early gene c-Fos, which can be a marker of cellular activity, across multiple brain regions. Recent evidence also suggests that abstinence from chronic intermittent alcohol exposure can produce mesoscale changes in c-Fos expression. However, there is a substantial gap in our understanding of how excessive drinking affects functional connectivity networks to influence alcohol-seeking behaviors. For this study, male and female C57BL/6J mice were given access to either water or a choice between water and ethanol in the intermittent access drinking model for 4 weeks. After a short-access drinking session, whole brains from high alcohol drinking male and female mice and water drinking controls were then subjected to c-Fos immunolabeling, iDISCO+ clearing, light sheet imaging, and whole-brain c-Fos mapping. Correlation matrices were then generated and graph theoretical statistical approaches were used to determine changes in functional connectivity across sex and drinking condition. We observed robust sex differences in the network of c-Fos+ cells in water drinking mice, and excessive alcohol drinking produce divergent and robust changes in functional network connectivity in male and female mice. In addition, these analyses identified novel hub regions in excessively drinking mice that were unique for each sex. In conclusion, the whole-brain c-Fos mapping analysis identified sex difference in functional network connectivity and unique and understudied regions that may play a critical role in controlling excessive ethanol drinking in male and female mice.

OBJECTIVE:Although gabapentin has demonstrated efficacy in mitigating alcohol withdrawal symptoms and preventing relapse drinking in individuals with alcohol use disorder (AUD), the neurobiological mechanisms of action underlying these therapeutic effects remain unknown. The present study evaluated changes in GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) as candidate mechanisms of action. METHODS:In a 16-week randomized clinical trial, 68 adults with AUD, including a history of alcohol withdrawal syndrome, received 1,200 mg/day of gabapentin (N=37) or placebo (N=31) and nine medical management visits after ≥72 hours of abstinence. Proton MR spectroscopy (1H-MRS) estimates of dACC levels of GABA (N=67) and glutamate (N=64) were acquired before start of treatment and again approximately 14 days after randomization. Percent days abstinent was reported via timeline followback interview. RESULTS:The effects of gabapentin on GABA and glutamate levels were significantly associated with participants' percent days abstinent during early treatment. Specifically, gabapentin was associated with greater increases in glutamate and greater decreases in GABA levels in participants who remained mostly or entirely abstinent, and yet the opposite in participants who drank on more than half of the days preceding the second scan. Furthermore, gabapentin-treated participants with greater increases in glutamate levels during early treatment had significantly more percent days abstinent across the remainder of the study, relative to placebo-treated participants. CONCLUSIONS:In addition to providing insight into the mechanisms through which gabapentin may promote abstinence in individuals with AUD, this study also provides evidence for a biomarker of efficacious treatment that may be used to evaluate other glutamatergic or GABAergic medications for AUD and related conditions.