Treatment Of Alcohol Use Disorders Research Articles

The Impact of Alcohol-Induced Epigenetic Modifications in the Treatment of Alcohol use Disorders.

Alcohol use disorders are responsible for 5.9% of all death annually and 5.1% of the global disease burden. It has been suggested that alcohol abuse can modify gene expression through epigenetic processes, namely DNA and histone methylation, histone acetylation, and microRNA expression. The alcohol influence on epigenetic mechanisms leads to molecular adaptation of a wide number of brain circuits, including the hypothalamus-hypophysis-adrenal axis, the prefrontal cortex, the mesolimbic-dopamine pathways and the endogenous opioid pathways. Epigenetic regulation represents an important level of alcohol-induced molecular adaptation in the brain. It has been demonstrated that acute and chronic alcohol exposure can induce opposite modifications in epigenetic mechanisms: acute alcohol exposure increases histone acetylation, decreases histone methylation and inhibits DNA methyltransferase activity, while chronic alcohol exposure induces hypermethylation of DNA. Some studies investigated the chromatin status during the withdrawal period and the craving period and showed that craving was associated with low methylation status, while the withdrawal period was associated with elevated activity of histone deacetylase and decreased histone acetylation. Given the effects exerted by ethanol consumption on epigenetic mechanisms, chromatin structure modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, might represent a new potential strategy to treat alcohol use disorder. Further investigations on molecular modifications induced by ethanol might be helpful to develop new therapies for alcoholism and drug addiction targeting epigenetic processes.

Daily cigarette smoking among inpatients for substance use disorders in France, 2010-2020: Commonalities and specificities across substances.

This study aims to estimate the prevalence and factors associated with cigarette smoking among patients in treatment for substance use disorders (SUD) in France. We analyze a nation-wide dataset retrieving information on patients entering treatment for alcohol, opioid and stimulant use disorders between 2010 and 2020. We conduct multilevel Poisson regressions to determine the main factors associated with daily cigarette smoking among all patients who entered treatment for alcohol (n=607122), opioid (n=283381) or stimulant (n=57189) use disorders, and zero-truncated negative-binomial regressions to predict the average number of cigarettes per day. Daily cigarette smoking remains a widespread behavior among patients with SUD (overall prevalence: 72.2%, 95% CI: 72.1-72.3), with lower prevalence of daily cigarette smoking among patients treated for alcohol use disorders (69.9%, 95% CI: 69.8-70.0), and higher for patients treated for opioid (78.8%, 95% CI: 78.6-79.0) or stimulant use disorders (75.8%, 95% CI: 75.4-76.2). There was an overall increase in daily cigarette smoking over time (69.9%, 95% CI: 69.8-70.0 in 2010 vs 76.8%, 95% CI: 76.5-76.9 in 2020); however, the average number of cigarettes per day decreased (17.8 per day, 95% CI: 17.7-17.9 in 2010 vs 16.3 per day, 95% CI: 16.2-16.4 in 2020). The higher the education level, the fewer number of cigarettes per day; conversely, the higher the occupational status, the higher the number of cigarettes. The high prevalence of smoking among patients treated for SUD in France departs from the decreasing trend observed in the general population and remains a source of concern. It is necessary to implement tailored prevention strategies that target specific patient subgroups and increase staff awareness.

Connectivity Changes Following Episodic Future Thinking in Alcohol Use Disorder.

Introduction: Recent addiction and obesity-related research suggests that episodic future thinking (EFT) can serve as a promising intervention to promote healthy decision-making. We used data from a pilot study to investigate the acute neural effects of EFT in alcohol use disorder (AUD). Because of the limitations of those data, we additionally used data from a previously published functional MRI (fMRI) study in which participants had not received any intervention for their AUD. Methods: In an out-of-scanner, guided interview, participants (n = 24; median age = 37.3 years; median AUDIT = 22.5) generated scenarios and cues about their future (EFT intervention, n = 15) or recent past (control episodic thinking [CET] control intervention, n = 9). Then, they performed both resting-state and task-based (delay discounting [DD]) fMRI. We used nodes from the default mode network and salience networks as well as the hippocampus to perform seed-based analyses of the resting-state data. The results then guided psychophysiological interaction analyses in the DD task. In addition, we used data from a larger, previously reported study as a "no intervention" group of AUD participants (n = 50; median age = 43.3; median Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) alcohol dependence score = 7) to reproduce and aid in interpreting our key findings. Results: EFT, but not CET, participants showed statistically improved DD rates-a behavioral marker for addiction. Resting-state analyses of the left hippocampus revealed connectivity differences in the frontal poles. The directionality of this difference suggested that EFT may reduce a hypo-connectivity relationship between these regions in AUD. We also found resting-state connectivity differences between the salience network and the right dorsolateral prefrontal cortex (R DLPFC), which then led us to discover R-to-L DLPFC psychophysiological interaction differences during DD. Moreover, the resting-state salience-to-DLPFC functional connectivity showed an inverse relationship to DD rate while hyperconnectivity between left and right DLPFC reflected slower reaction times during DD trials. Discussion: These findings suggest that previously noted benefits of EFT such as the improved DD replicated here might coincide with changes in neural connectivity patterns in AUD. The alterations in connectivity highlight potential mechanisms underlying the effectiveness of EFT in improving decision-making in AUD. Understanding these neural effects may contribute to the further development of targeted interventions for AUD and related disorders.

Disparities in Treatment for Alcohol Use Disorder Among All of Us Participants.

The authors examined racial/ethnic and socioeconomic disparities in receiving treatment for alcohol use disorder (AUD). A retrospective cohort study was conducted that included adults (≥18 years) with AUD from the All of Us Controlled Tier database v7. Outcomes were lifetime receipt of FDA-approved medications (disulfiram, acamprosate, and naltrexone), psychotherapy (individual, family, and group-based session), and combination treatment (medication and psychotherapy). The study examined treatment receipt by race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, other), insurance (private, Medicare, Medicare and Medicaid, Medicaid, Veteran Affairs [VA], none), income (<$10K, $10-<$50K, $50-$100K, >$100K), and area deprivation index (ADI) quintiles. Multivariable logistic and multinomial logistic regressions were used to assess the association between patient characteristics and treatment receipt. The cohort consisted of 18,692 patients (mean age=57.1 years; 60.7% were male; 47.1% were non-Hispanic White). Almost 70% received no treatment, 11.4% received medication, 24.0% received psychotherapy, and 4.9% received combination treatment. In adjusted analysis, non-Hispanic Black (aOR=0.78, 95% CI=0.69-0.89) and Hispanic (aOR=0.75, 95% CI=0.64-0.88) individuals were less likely to receive medication than non-Hispanic White counterparts. There was no association between race/ethnicity and receipt of psychotherapy or combination treatment. Compared with private insurance, dual eligibility was associated with less use of medication, Medicare and Medicaid with less use of medication and combination treatment, and VA and no insurance with more use of psychotherapy and combination treatment. Higher income and lower ADI were positively associated with all treatment types. There are disparities in AUD treatment by race/ethnicity, socioeconomic status, and insurance. Systematic approaches are required to improve equitable access to effective treatment.

Results from a randomized controlled trial of zonisamide in the treatment of alcohol use disorder

There is preliminary evidence that the anticonvulsant medication Zonisamide (ZON) may be an effective, well-tolerated treatment for alcohol use disorder (AUD). However, further evaluation of its efficacy for treating patients with AUD is needed, and much remains unknown about ZON’s therapeutic mechanisms. The present study aimed to evaluate the efficacy and tolerability of ZON in a double-blind, placebo-controlled, randomized trial. Eighty-one adults (ages 21-65) diagnosed with AUD were randomly assigned to receive either ZON (at a target dose of 400 mg/d) or a pill placebo over 12 weeks, followed by a two-week taper. All participants also received a computerized alcohol reduction program, Take Control (TC). Primary drinking outcomes were average daily drinks, percentage drinking days, and percentage heavy drinking days. Further, we evaluated changes in AUD clinical severity and performance on neuropsychological measures. For both groups, drinking outcomes generally decreased, as did AUD clinical severity, though group differences were not statistically significant. Neuropsychological testing performance was similar for both groups at baseline; however, at post-treatment, participants in the ZON group demonstrated poorer working memory and lower performance on verbal fluency tests compared to the placebo group, and these differences were statistically significant with moderate-large effect sizes. One serious adverse event was reported among individuals receiving ZON. Study findings indicate that ZON combined with TC does not demonstrate superior effectiveness for reducing average daily drinks in this clinical sample with principal AUD compared to placebo and TC, and treatment with ZON may be associated with reduced neurocognitive performance over time.

Biased allosteric modulator of neurotensin receptor 1 reduces ethanol drinking and responses to ethanol administration in rodents

Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse is the 7th leading cause of premature death [1]. Despite this, there are currently only 3 FDA approved pharmacological approaches for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant use. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, physiological sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.

Probenecid as a pharmacotherapy for alcohol use disorder: Arandomized placebo-controlled alcohol interaction trial.

This study shows the first evidence for pannexin 1 channels as a new target to develop medications for alcohol use disorder (AUD). Due to its history of long-term safe clinical use and preclinical evidence of reducing excessive alcohol intake in rodents, probenecid has clinical potential for AUD. We conducted a Phase I/IIa randomized, double-blind, placebo-controlled, crossover trial investigating the safety, tolerability, and efficacy of an oral dose of probenecid (2 g) when administered with alcohol (0.08 g/dL) in individuals who regularly consume alcohol to the 0.08 g/dL level (N = 35) and in individuals with mild to severe AUD. Alcohol pharmacokinetics and subjective responses were evaluated to assess potential interactions between probenecid and alcohol. Alcohol craving, inflammatory biomarkers, cognitive assessments, and hemodynamics were assessed as additional alcohol research domains. All outcomes were assessed both in the ascending and descending limb of alcohol intoxication using Generalized Estimating Equation. Probenecid did not exert any significant effect on alcohol pharmacokinetics and did not affect alcohol stimulation or sedation. Probenecid, compared to placebo, significantly decreased alcohol craving during the alcohol ascending limb. Inflammatory biomarkers, cognitive performance following alcohol ingestion, and hemodynamics were likewise not affected by probenecid administration. Analysis of sex as a biological variable revealed no differences of probenecid compared to placebo. Taken together, our data support the potential of probenecid for treatment of AUD and suggest that pannexin 1 channels represent a novel emerging therapeutic target for the development of new pharmacotherapies for treating AUD.

Recovery of Executive Functions in Alcohol Use Disorder: role of Neuropsychological Rehabilitation

Abstract Background Alcohol Use Disorder (AUD) is a growing public health concern with high incidence of executive functions (EFs) changes, affecting disease progression and treatment effectiveness. Inconsistencies persist in studies on the role of neuropsychological rehabilitation (NR) in EF recovery within AUD interventions. Our aim is to analyse the effect of NR on EFs in AUD interventions. Methods A prospective cohort study included 65 participants of both sexes, diagnosed with AUD, free of psychiatric comorbidities or severe neurological conditions. They underwent alcohol detoxification in hospital/home from 2021 to 2023, completing three evaluation moments (M1-Baseline, M2-3 months, M3-6 months). Patients receiving usual treatment (WTG-weekly therapeutic groups) - were compared to those with additional Neuropsychological Rehabilitation (NRG) regarding Sociodemographic and Severity of Alcohol Dependence Questionnaires, Hospital Anxiety and Depression Scale, Frontal Assessment Battery (FAB), Number and Letters Subscale of Weschler Adult Intelligence Scale (WAIS). Our main outcome was FAB-general executive functioning, and secondary outcome was WAIS-working memory. Friedman test compared assessments across the three points (alpha 5%). Results Statistically significant differences were found for FAB in both groups, (p &amp;lt; 0.001) between M1 and both M2 and M3, indicating improved executive functioning, particularly in NRG. Working memory also improved in both groups (WTG: p = 0.036; NRG: p &amp;lt; 0.001), with NRG showing better M2 performance. Conclusions There is evidence that neuropsychological rehabilitation facilitates the recovery of executive functions and may play a pivotal role in relapse prevention. It is crucial that the treatment of these situations incorporates public health, preventive and damage minimization measures. KeyWords: Executive Function; Neuropsychological Rehabilitation; Alcohol Use Disorder. Key messages • Recovery of executive functions is crucial from a Public Heath perspective in AUD populations, minimizing morbidity, permanent disabilities and contributing to more effective healthcare services. • Integrating Neuropsychological Rehabilitation into standard Alcohol Use Disorder treatments can enhance treatment effectiveness, reducing disease burden.

Insomnia treatment effects on negative emotionality among veterans in treatment for alcohol use disorder.

Insomnia symptoms are pervasive and persistent in alcohol use disorder (AUD), though little is known about the mechanisms that underlie this association. We previously found that cognitive behavioral therapy for insomnia (CBT-I) reduced alcohol-related problems among veterans by improving insomnia severity (NCT03806491). In this planned secondary analysis of the same clinical trial data, we tested negative emotionality as one potential mechanism to explain this effect. Specifically, we tested the change in negative emotionality as a mediator of the association between change in insomnia symptoms and alcohol-related outcomes (craving, heavy drinking frequency, and alcohol-related problems). Participants were 67 veterans in treatment for AUD who also met the criteria for insomnia disorder (91% male, 84% White, average age = 46.3 years). Participants were randomized to five sessions of CBT-I or a single-session sleep hygiene control. Assessments occurred at baseline, immediately posttreatment (~6 weeks after baseline), and at 6-week follow-up. Measures included the Insomnia Severity Index, Penn Alcohol Craving Scale, Timeline Followback, and Short Inventory of Problems. We created a latent negative emotionality indicator based on five validated and reliable measures of negative emotionality. Contrary to hypotheses, CBT-I did not improve negative emotionality relative to sleep hygiene control. However, across both treatment conditions, decreases in insomnia symptoms from baseline to posttreatment were associated with concurrent decreases in negative emotionality, which in turn predicted reductions in alcohol craving and heavy drinking. Negative emotionality may help explain links between insomnia symptoms and alcohol-related outcomes.

Popular weight‐loss medications could have applications for SUD

Two categories of medications that have soared in popularity in addressing weight loss could eventually become impactful strategies in the treatment of opioid use disorder (OUD) and alcohol use disorder (AUD). But the findings that suggest this potential has been observational to this point, meaning more targeted trials will be necessary before these therapies can be seen as a breakthrough.

Systematic review on resting-state fMRI in people with AUD and people who binge drink.

Resting-state functional magnetic resonance imaging (rsfMRI) has become ubiquitous in neuroimaging to study disorders, including alcohol use disorder (AUD), given its potential to serve as a biomarker of psychiatric symptoms. The number of techniques, sample heterogeneity, and findings demand the assessment of results to identify potential biomarkers for the development of treatment. This systematic review aimed to synthesize the alcohol rsfMRI literature by summarizing the results by analysis approach and groups to examine these findings in the context of the neurobiology of addiction model. Three databases were systematically searched, resulting in the inclusion of 17 studies with a total of 784 participants (387 were people with AUD, 38 engaged in binge drinking, and 359 were controls). Seed-based functional connectivity studies were the most prominent. Compared to controls, people who binge drink and people with AUD showed greater connectivity of the Middle Frontal Gyrus-a region associated with the preoccupation/anticipation stage of the theory. Regions of the prefrontal and limbic cortex were most consistently reported in studies. The different types of analyses, sample size, and variability in the sample may have contributed to differences reported across studies. This review synthesizes and examines the results of different studies using the neurobiology of addiction theory, which may inform future studies on potential regions of interest, recruitment approaches, and analysis methods. Standardizing the methods for such a heterogeneous population could lead to more rapid development of neurobiologically-informed treatments for AUD.

Patient Perspectives on Blended Internet-Based and Face-to-Face Cognitive Behavioral Therapy for Alcohol Use Disorder: Qualitative Study.

Harmful alcohol consumption has been identified as a major contributor to disease, mortality, and social harm, accounting for 5.3% of worldwide deaths annually. In Denmark, an estimated 150,000 people suffer from alcohol use disorder (AUD), but a low proportion seek treatment due to person- and treatment-related barriers. Internet-based cognitive behavioral therapy (iCBT) has shown positive effects on the treatment gap, with patients reporting benefits such as increased knowledge and flexibility. However, there is a lack of research on blended cognitive behavioral therapy (bCBT), which combines face-to-face CBT (FtF CBT) and iCBT for AUD. This study aims to investigate user experiences of bCBT. More specifically, it seeks to explore the advantages and disadvantages that users have experienced with bCBT for AUD, as well as their motivations for choosing this treatment format. A total of 30 patients who had participated in the Blend-A (Blending Internet Treatment into Conventional Face-to-Face Treatment for AUD) study and received the intervention were contacted and offered the opportunity to participate in semistructured individual telephone interviews. Of these, 12 patients consented to participate. Furthermore, an additional participant was approached at a municipal clinic and agreed to engage in an individual FtF interview. Thus, the final sample consisted of 13 patients. The interviews explored their background, experiences with digital technology, motivations for choosing internet-based treatment, and experiences with the program during AUD treatment. The interviews were audio-recorded and transcribed in full length and analyzed using thematic analysis. All data were anonymized and securely stored. We found that users experienced several advantages of iCBT over a larger part of the treatment course, including increased anonymity and privacy. Most importantly, it offered flexibility, allowing patients to focus on their rehabilitation process at their own pace. Patients appreciated the availability of written text in the online program, finding it helpful for gaining knowledge and understanding of AUD and its impact on the individual with the condition. They emphasized how the assignments helped them fully engage in treatment by first acknowledging their problem with alcohol and then dedicating time to self-reflection before FtF sessions, allowing for more in-depth discussions with the therapist. They also appreciated the reminders, which motivated them to complete their assignments. Overall, patients perceived more benefits than disadvantages in using bCBT. Essentially, bCBT offers a form of assisted autonomy that cannot be fully achieved through iCBT or FtF CBT alone. It is only through their combination that patients can fully appreciate the benefits of the treatment, as they have time for self-reflection, with guidance from the therapist between FtF CBT sessions. ClinicalTrials.gov NCT04535258; https://clinicaltrials.gov/ct2/show/NCT04535258.

Co-created improvement goals and strategies for implementing SBIRT and MAUDin primary care settings in a facilitator-supported, tailored implementation study.

Evidence-based approaches to screening and treatment for unhealthy alcohol use have the potential to reduce morbidity and mortality but are currently underutilized in primary care settings. To support implementation of screening, brief intervention, and referral to treatment (SBIRT) and medication-assisted treatment for alcohol use disorder (MAUD) by identifying goals co-developed by clinics and practice facilitators in a flexible implementation study. In a pragmatic implementation study, we used practice facilitation to support the implementation of SBIRT and MAUD in 48 clinical practices across Oregon, Washington, and Idaho. Our study used a tailored approach, in which facilitators and clinics co-identified implementation goals based on clinic needs. We used clinic contact logs, individual interviews, group periodic reflections with practice facilitators, and exit interviews with clinic staff to inform qualitative analysis. With support from practice facilitators, clinics identified goals spanning SBIRT, MAUD, reporting, targeted patient outreach, and quality improvement capacity. Goals addressed both the technical (e.g. data tracking) and social (e.g. staff training) aspects of SBIRT and MAUD. A decision tree summarizes emergent findings into a tool to support future implementation of SBIRT in primary care settings. A facilitator-supported, tailored approach to SBIRT implementation enabled clinics to identify a variety of goals to improve SBIRT and MAUD implementation. These identified priorities, along with a decision tree describing the hierarchical structure of these goals, could support future implementation efforts.

Advances in research on medications for the treatment of alcohol use disorders: A review.

Alcohol use disorder (AUD) has become a global public health challenge, with the social and economic costs of alcohol abuse escalating, drawing widespread attention from healthcare professionals and the public worldwide. Particularly in recent years, the COVID-19 pandemic and associated lockdown measures have led to a significant increase in global alcohol consumption, further exacerbating the risk of AUD and sparking in-depth discussions on its prevention and treatment methods. Given that the current mainstay of AUD treatment relies on pharmacotherapy, the aim of this article is to review the progress of existing drug research for the treatment of AUD, and at the same time to focus on drug classes that have not yet been applied to the clinic, but have been shown in recent studies to be potentially exploitable for the treatment of AUD, in order to provide new ideas and directions for future drug research and development efforts.

Effectiveness and experience of implementing digital interventions to promote smoking cessation among adults with severe mental illness: A systematic review and meta-analysis.

Digital technology is increasingly used to support interventions targeting smoking cessation in people with severe mental illness (SMI). However, little is known about their implementation and effectiveness in this population. We aimed to determine their effectiveness, stakeholder experiences, factors influencing implementation, and quality of reporting of digital interventions for smoking cessation in adults living with SMI. Five online bibliographic databases were searched for articles published between 31 December 2000 and 31 January 2023. Studies involving adults accessing treatment for alcohol and substance use disorders, neurocognitive disorders and terminal illnesses were excluded. Risk of bias was assessed using the Mixed Methods Appraisal Tool (MMAT). A Mantel-Haenszel random-effects meta-analysis of randomized controlled trials (RCTs) was conducted. Participant experience and intervention implementation were explored using a narrative synthesis. Quality of reporting of interventions was assessed using the Template for Intervention Description and Replication (TIDieR) checklist. Thirty-one studies enrolling 3,794 participants were included. Meta-analysis of biochemically verified abstinence at longest follow-up (month-1 to month-6) did not find an overall effect in favour of intervention [risk ratio (RR) = 0.66, 95% confidence interval (CI) = -0.005 - 1.37]. Interventions tailored to people with SMI were perceived as acceptable. Implementation strategies concentrated on overcoming practical challenges at the participant/user level. No evidence of the effectiveness of digital interventions to support smoking cessation in people with SMI was found. The importance of tailoring interventions to the needs of people with SMI is highlighted. Robust reporting of implementation is required to enhance future efforts to support smoking cessation in adults with SMI. The findings of this review add to the emerging evidence on digital interventions to support smoking cessation among people with SMI. We highlight the importance of tailoring interventions to the population, particularly considering the role of mental illness and the side effects of psychotropic medication in the accessibility and usability of digital interventions.

Individualized Assessment and Treatment Program (IATP) for alcohol use disorder: Comparison with conventional cognitive-behavioral treatment and examination of coping skills as a mediator of treatment.

This study tested a highly individualized cognitive-behavioral coping skills treatment for alcohol use disorder (AUD). Recent studies have indicated that coping skills training programs are not always effective. A possible explanation is that the training provided in these programs may not address the specific needs of the patient. The Individualized Assessment and Treatment Program (IATP) was intended to provide a highly individualized approach to the training of skills most relevant for each individual. Men and women with AUD (N = 173) were randomly assigned to one of three, manualized, 12-session treatments: IATP, a conventional (Packaged) cognitive-behavioral program (PCBT), or a Case Management control condition (CaseM). An experience sampling (ES) procedure was employed prior to, and during, treatment to record alcohol use and coping behaviors in all patients. In IATP, this information was used by therapists to plan treatment that would address the specific strengths and weaknesses of each patient in alcohol-use situations. ES data were collected at multiple time points and patients were followed every 3 months out to 21 months posttreatment. Multilevel model analyses indicated that IATP yielded better drinking outcomes than the CaseM or PCBT conditions. Mediation analyses indicated that the effects of IATP versus the other treatments on outcomes were accounted for at least partly by changes in active coping with high-risk situations. Due to the limited diversity of the sample, generalizability of the results may be limited. Results are discussed in terms of the importance of tailoring treatment for the individual patient. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Chronic ethanol exposure in mice evokes pre- and postsynaptic deficits in GABAergic transmission in ventral tegmental area GABA neurons.

GABAergic neurons in mouse ventral tegmental area (VTA) exhibit elevated activity during withdrawal following chronic ethanol exposure. While increased glutamatergic input and decreased GABAA receptor sensitivity have been implicated, the impact of inhibitory signaling in VTA GABA neurons has not been fully addressed. We used electrophysiological and ultrastructural approaches to assess the impact of chronic intermittent ethanol vapour exposure in mice on GABAergic transmission in VTA GABA neurons during withdrawal. We used CRISPR/Cas9 ablation to mimic a somatodendritic adaptation involving the GABAB receptor (GABABR) in ethanol-naïve mice to investigate its impact on anxiety-related behaviour. The frequency of spontaneous inhibitory postsynaptic currents was reduced in VTA GABA neurons following chronic ethanol treatment and this was reversed by GABABR inhibition, suggesting chronic ethanol strengthens the GABABR-dependent suppression of GABAergic input to VTA GABA neurons. Similarly, paired-pulse depression of GABAA receptor-dependent responses evoked by optogenetic stimulation of nucleus accumbens inputs from ethanol-treated mice was reversed by GABABR inhibition. Somatodendritic currents evoked in VTA GABA neurons by GABABR activation were reduced following ethanol exposure, attributable to the suppression of GIRK (Kir3) channel activity. Mimicking this adaptation enhanced anxiety-related behaviour in ethanol-naïve mice. Chronic ethanol weakens the GABAergic regulation of VTA GABA neurons in mice via pre- and postsynaptic mechanisms, likely contributing to their elevated activity during withdrawal and expression of anxiety-related behaviour. As anxiety can promote relapse during abstinence, interventions targeting VTA GABA neuron excitability could represent new therapeutic strategies for treatment of alcohol use disorder.

Centrally administered growth hormone secretagogue receptor antagonist DLys decreases alcohol intake and preference in male mice.

Alcohol use disorder (AUD) is a highly prevalent public health problem. The ghrelin system has been identified as a potential target for therapeutic intervention for AUD. Previous work showed that systemic administration of the growth hormone secretagogue receptor (GHSR) antagonist DLys reduced alcohol intake and preference in male mice. Yet, it is unclear whether central or peripheral GHSRs mediated these effects. We hypothesized that alcohol consumption is driven by central GHSRs and addressed this hypothesis by testing the effects of central administration of DLys. Male C57BL/6J mice consumed alcohol in a two-bottle choice procedure (10% ethanol versus water). DLys (2 nmol) was administered intracerebroventricularly for 7 days to examine alcohol intake and preference. DLys decreased alcohol intake and preference but had no effect on food intake. The effects on alcohol intake and preference persisted after several administrations, indicating lack of tolerance to DLys' effects. These results suggest that central administration of DLys is sufficient to reduce alcohol drinking and that DLys remains effective after several administrations when given intracerebroventricularly. Moreover, this work suggests that the effects of intracerebroventricularly administered DLys are specific to alcohol and do not generalize to other calorie-driven behaviors.

Was receipt of any specialty alcohol treatment during the pandemic effective at reducing drinking for patients with or at risk of AUD?

IntroductionThe COVID-19 pandemic changed the way healthcare providers delivered most health services, including treatment for alcohol use disorder (AUD). Specialty alcohol treatment remained available through the pandemic, and within some systems treatment use increased likely due to telehealth availability. However, the field knows little about the relationship between the pandemic's expanded access to specialty alcohol treatment and alcohol use outcomes. MethodsThe sample included 14,712 patients from Kaiser Permanente Northern California who screened positive for unhealthy alcohol use in primary care and had an AUD diagnosis or risked developing an AUD by reporting 5 or more heavy drinking days in a 3-month period between 1/1/2019 and 2/29/2020 (pre-pandemic). The study examined the receipt of any specialty alcohol treatment (including at least one outpatient, inpatient, or telehealth specialty treatment encounter, or pharmacotherapy prescription) from 3/1/2020 (pandemic start) to either the first completed follow-up alcohol screening or 6/20/2022 (study period end). The outcomes of alcohol use included changes in heavy drinking days, drinks per week, drinking days per week, and drinks per drinking day between the pre- and post-pandemic periods. ResultsOn average patients significantly decreased alcohol use across all four alcohol use measures examined, regardless of whether they received treatment. However, those who received any treatment compared to those who did not have greater reductions in alcohol use, with an additional decrease of −3.55 heavy drinking days (95 % CI = −5.93, −1.17), −3.80 drinks per week (95 % CI = −5.18, −2.42), −0.72 drinks per drinking day (95 % CI = −1.14, −0.30), and − 1.01 drinking days per week (95 % CI = −1.30, −0.72). Treatment effects were greatest among patients who exceeded both daily and weekly limits pre-pandemic, with an additional decrease of −10.75 heavy drinking days (95 % CI = −15.28, −6.21), −12.83 drinks per week (95 % CI = −16.31, −9.35), −1.67 drinks per drinking day (95 % CI = −2.19, −1.14), and −2.02 drinking days per week (95 % CI = −2.41, −1.63). ConclusionsOn average, patients decreased alcohol use during the onset of the pandemic, however, those who had any specialty alcohol treatment had significantly greater decreases, suggesting that the hybrid in-person and telehealth treatment approach was effective during the pandemic.

Binge ethanol consumption can be attenuated by systemic administration of minocycline and is associated with enhanced neuroinflammation in the central amygdala

Alcohol use disorder (AUD) has a complicated pathophysiology. Binge ethanol intoxication may produce long-lasting changes throughout extended amygdala neurocircuitry including neuroinflammation, often leading to relapse. Therefore, understanding the role of binge drinking induced neuroinflammation on extended amygdala neurocircuitry is critically important for treatment. We sought to understand the role of neuroinflammation in a naturalized form of rodent binge ethanol drinking (Drinking in the Dark (DID)). In a 5-week DID paradigm, we demonstrate that acute intraperitoneal (IP) injection of the anti-inflammatory drug minocycline significantly reduced binge drinking repeatedly in male and female Cx3CR1-GFP and C57BL/6J mice. Importantly, IP administration transiently decreased intermittent access sucrose consumption, was not observed on the second IP injection, but did not significantly alter food or water consumption, suggesting that minocycline may produce initial acute aversive effects and may not alter long-term consumption of natural rewards. Examination of rodent behaviors post ethanol binge drinking reveals no lasting effects of minocycline treatment on locomotion or anxiety-like behavior. To assess neuroinflammation, we developed a novel analysis method using a Matlab image analysis script, which allows for non-biased skeletonization and evaluation of microglia morphology to determine a possible activation state in Cx3CR1-GFP knock-in mice after repeated DID. We observed significant morphological changes of microglia within the CeA, but no differences in the BLA. Taken together, this study demonstrates repeated binge ethanol consumption can produce significant levels of microglia morphology changes within the CeA, and that immunomodulatory therapies may be an intriguing pharmacological candidate for the treatment of AUD.