alcohol

A Double-Blind Randomized Controlled Trial of Daridorexant for Alcohol Use Disorder

Project Summary/Abstract This R01 application proposes integrating a randomized, double-blinded, placebo-controlled clinical trial into a real-world treatment setting to test whether the dual orexin receptor antagonist (DORA) daridorexant reduces alcohol craving and use and improves total sleep time among patients with alcohol use disorder (AUD) and co-occurring sleep disturbance. DORAs have shown promise in modulating reward and reducing alcohol self- administration in preclinical models. Further, DORAs are FDA-approved for insomnia, are highly efficacious for treatment of sleep disturbance, have a favorable safety profile, and demonstrate low abuse liability. Thus, DORAs are a highly promising treatment for AUD, particularly among persons that have co-occurring sleep disturbance. To this end, the proposed study will recruit individuals from a residential treatment facility, following completion of medically managed withdrawal and stabilization. Eligible participants will be randomized to daridorexant to placebo, and will complete measures of alcohol craving, total sleep time (assessed through both wireless electroencephalography and biometric data collection), and adverse events. Following discharge from residential treatment, participants will continue taking the study medication for two weeks while submitting daily reports of alcohol use, alcohol craving, sleep diaries, and biometric sleep data. Participants will also be prompted to submit three-times weekly random breath alcohol level using a portable BACtrack S80 breathalyzer, and will attend weekly check-in visits to assess adverse events and to confirm daily alcohol reports. A one-month follow-up assessment will be conducted to collect long-term data on alcohol use, AUD symptoms, and sleep. Ultimately, this study has the potential to identify a novel treatment for co- occurring AUD and sleep disturbance, and will address the following specific aims: (1) Test whether daridorexant reduces alcohol craving and post-treatment alcohol use relative to placebo. (2) Test whether daridorexant improves objectively measured total sleep time relative to placebo. (3) Examine the frequency of adverse events in persons assigned to daridorexant relative to placebo. If these aims are supported, then we will also explore whether effects are moderated by insomnia severity. We will also examine if the effects replicate across residential environments (with structured sleep/wake times and close monitoring of medication adherence) and outpatient environments (with self-imposed sleep/wake times and self-dosing). Currently, there are no FDA approved medications indicated for both AUD and insomnia. This innovative strategy aims to address a critical gap by investigating the effectiveness of daridorexant in modulating alcohol craving and alcohol use. This study will contribute to a growing literature on the role of the orexin system in reward and alcohol use.

FIRE-PF: Developing and Testing a Trauma-Informed Alcohol Intervention to Enhance Mental Health in Firefighters

PROJECT SUMMARY Alcohol use and hazardous drinking are ubiquitous among firefighters in the United states and is associated with significant physical and mental health risks for this population. Due to the nature of their work, firefighters experience substantially higher rates of trauma exposure and are subsequently at greater risk of developing specific mental health conditions compared to the general population, particularly trauma-related psychopathology (e.g., posttraumatic stress). Hazardous drinking and posttraumatic stress frequently co-occur among firefighters, leading to poorer health outcomes compared to either condition alone. Despite this elevated risk, firefighters often lack access to tailored, empirically supported interventions, and no existing mental health interventions address hazardous drinking in a trauma-informed framework for this at-risk population. Personalized feedback interventions (PFIs) are a promising approach that could address this gap. By delivering brief, patient-centered feedback on drinking behaviors and perceptions within the context of trauma and occupational stress, PFIs aim to reduce problematic drinking behaviors and stigma related to coping-orientated drinking and improve stress management strategies. PFIs can be brief, cost-effective, and easily disseminated in a format accessible to large groups, making them a strong candidate for use with firefighters who face critical barriers to engaging in traditional mental health programs. This innovative study aims to develop a single-session, trauma-informed, online PFI tailored specifically for firefighters, using a comprehensive, three-phase approach to address three primary aims. The Development Phase involves developing, adapting, and enhancing a trauma-informed PFI by gathering qualitative feedback from firefighters (N = 45) and using an iterative, rapid user-centered design approach to ensure the intervention is engaging for firefighters as well as relevant and aligned with fire service culture. The Evaluation Phase will assess the feasibility, acceptability, and preliminary impact of the PFI in a mixed-methods longitudinal open trial with firefighters (N = 50), with a focus on the intervention's usability, delivery, and influence on drinking behaviors. The Implementation Planning Phase will involve qualitative and quantitative assessments with fire service leaders (N = 15) to identify implementation barriers and shape future research testing the implementation process for the intervention and inform future strategies for resource integration and fostering sustainable community partnerships. This proposal will equip Dr. Lebeaut with essential training for an independent research career, including training in (1) qualitative methodologies, (2) user-centered design, (3) developing, adapting, and enhancing trauma-informed alcohol interventions, and (4) developing collaborative relationships with community partners in the fire service. The proposed study will directly inform a future R01 to evaluate the intervention’s efficacy and scalability and support the development of a firefighter-focused research program.

Basal Ganglia in addiction

Dopamine receptors dysregulation in BG disease

Elucidating the mechanism underlying Stress and Caffeine-induced motor dysfunction using a mouse model of Episodic Ataxia Type 2

Episodic Ataxia type 2 (EA2), caused by mutations in the CACNA1A gene, results in a loss-of-function of the P/Q type calcium channel, which leads to baseline ataxia, and attacks of dyskinesia, that can last a few hours to a few days. Attacks are brought on by consumption of caffeine, alcohol, and physical or emotional stress. Interestingly, caffeine and stress are common triggers among other episodic channelopathies, as well as causing tremor or shaking in otherwise healthy adults. The mechanism underlying stress and caffeine induced motor impairment remains poorly understood. Utilizing behavior, and in vivo and in vitro electrophysiology in the tottering mouse, a well characterized mouse model of EA2, or WT mice, we first sought to elucidate the mechanism underlying stress-induced motor impairment. We found stress induces attacks in EA2 though the activation of cerebellar alpha 1 adrenergic receptors by norepinephrine (NE) through casein kinase 2 (CK2) dependent phosphorylation. This decreases SK2 channel activity, causing increased Purkinje cell irregularity and motor impairment. Knocking down or blocking CK2 with an FDA approved drug CX-4945 prevented PC irregularity and stress-induced attacks. We next hypothesized caffeine, which has been shown to increase NE levels, could induce attacks through the same alpha 1 adrenergic mechanism in EA2. We found caffeine increases PC irregularity and induces attacks through the same CK2 pathway. Block of alpha 1 adrenergic receptors, however, failed to prevent caffeine-induced attacks. Caffeine instead induces attacks through the block of cerebellar A1 adenosine receptors. This increases the release of glutamate, which interacts with mGluR1 receptors on PC, resulting in erratic firing and motor attacks. Finally, we show a novel direct interaction between mGluR1 and CK2, and inhibition of mGluR1 prior to initiation of attack, prevents the caffeine-induced increase in phosphorylation. These data elucidate the mechanism underlying stress and caffeine-induced motor impairment. Furthermore, given the success of CX-4945 to prevent stress and caffeine induced attacks, it establishes ground-work for the development of therapeutics for the treatment of caffeine and stress induced attacks in EA2 patients and possibly other episodic channelopathies.

Role of the gut microbiota in the development of alcohol use disorder

The gut microbiota is composed of a very large number of bacteria, viruses, fungi and yeasts that play an important role in the body, through the production of a series of metabolites (including neurotransmitters), and through an essential role in the barrier function of the gut and the regulation of immunity and stress response. In this lecture I will present, based mainly on human studies but also on preclinical studies, the evidence for a role of the gut microbiota in the development of alcohol use disorder. I will show the first results of trials to test the effects of nutritional approaches to address these deficits.

Promising Neuroimmune Targets for Alcohol Use Disorder Pathology

Striatal mechanisms underlying vulnerability for punishment-resistant alcohol drinking

Schizophrenia and Substance Use Disorders: Cracking the Chicken-or-Egg Question

Although substance use disorders (SUDs) occur commonly in patients with schizophrenia and significantly worsen their clinical course, the neurobiological basis of SUDs in schizophrenia is not well understood. Therefore, there is a critical need to understand the mechanisms underlying SUDs in schizophrenia in order to identify potential targets for therapeutic intervention. Since drug use usually begins in adolescence, it is also important to understand the long-term effects of adolescent drug exposure on schizophrenia- and reward- related behaviors and circuitry. This talk will combine pharmacological, behavioral, electrophysiologic (local field potential recordings) and pre-clinical magnetic resonance imaging (resting-state functional connectivity and magnetic resonance spectroscopy) approaches to study these topics with an eye toward developing better treatment approaches.

Social deprivation, coping and drugs: a bad cocktail in the COVID-19 era: evidence from preclinical studies

The factors that underlie an individual’s vulnerability to switch from controlled, recreational drug use to addiction are not well understood. I will discuss the evidence in rats that in individuals housed in enriched conditions, the experience of drugs in the relative social and sensory impoverishment of the drug taking context, and the associated change in behavioural traits of resilience to addiction, exacerbate the vulnerability to develop compulsive drug intake. I will further discuss the importance of the acquisition of alcohol drinking as a mechanism to cope with distress as a factor of exacerbated vulnerability to develop compulsive alcohol intake. Together these results demonstrate that experiential factors in the drug taking context, which can be substantially driven by social isolation, shape the vulnerability to addiction.

Activity alterations of various brain regions in Alcohol intoxicated drivers: a systematic review and Meta analysis of functional magnetic resonance imaging studies

Alcohol Use Disorder Severity is Linked to Altered Functional Connectivity in Default Mode, Salience and Executive Control Networks

Pay attention to this change: Lateral Hypothalamic GABAergic neurons in attention and alcohol memories

Axonal pathology in alcohol use disorders

Beneficial effects of prolonged 2-phenylethyl alcohol inhalation on altered feeding behavior and neural activity in chronically distressed female mice

Cerebellar gradient of volume reduction in Fetal Alcohol Syndrome: toward a neuroanatomical marker?

The effect of cocaine and alcohol poly-consumption on drug seeking behavior in young adult rats

Effects of the monoamine stabilizer OSU6162 on compulsive alcohol-related behavior in rats

Fecal Microbiota Transfer reduces alcohol preference in stressed rats

Galanin (1-15) and escitalopram combination in rats reduces alcohol consumption in the ethanol self-administration test and improves escitalopram effects in the forced swimming test

Individual differences in dopamine neural dynamics predict voluntary alcohol drinking

Long-term consequences of alcohol use in early adolescent mice : focus on neuroadaptations in GR, CRF and BDNF

Long-term Effects of Maternal Separation on alcohol intake and acute stress response in male and female mice

Melatonin Reduces Alcohol Drinking in Rats with Disrupted Function of the Serotonergic System

Mice expressing allelic variant or deletion of CHRNA5 show increased alcohol consumption but opposite motivational profiles: preclinical support for Cloninger alcoholic subtypes

Modulation of N-acylethanolamines – peroxisome proliferator receptor type gamma axis counteracts memory deficits of prenatal and lactation alcohol exposed mice

A neural circuit for controlling long-term voluntary alcohol consumption

Neurophysiological correlates of sub-dimensions of alcohol use disorder in rodents

Psychometric profile, heterogeneity, and intellectual functioning in fetal alcohol spectrum disorder

The role of the nucleus accumbens shell in alcohol use despite negative consequences

Simultaneous prenatal alcohol and cannabinoid exposure during the second trimester augments reductions in fetal cerebral blood flow from alcohol exposure alone

Social emotional profiles of two strains of transgenic mice expressing nicotinic receptor mutations involved in alcohol abuse

Subthalamic nucleus deep brain stimulation reduces alcohol intake in rats under influence of proximal social factors

Ventral pallido-subthalamic adaptations underlying pathological decision making in alcohol use disorders

Voluntary alcohol consumption alters the neurobiology underlying cocaine-seeking

Alcohol perturbed locomotor behavior, metabolism, and pharmacokinetics of methamphetamine in rats

FENS Forum 2024

BMAL1 in the dorsomedial striatum affects alcohol consumption, affective behavior, and motor function sex-specifically in mice

FENS Forum 2024

Chronic alcohol intoxication induces social dominance and aggressive behavior in male mice: Mechanistic and therapeutic approach

FENS Forum 2024

Combined treatment with the glycine transporter-1-inhibitor Org24598, varenicline, and bupropion as a new pharmacological treatment concept for alcohol use disorder

FENS Forum 2024

Different mechanisms underlie compulsive alcohol self-administration in male and female rats

FENS Forum 2024

Differential neuroinflammatory responses to immune challenges in male and female rats prenatally exposed to alcohol

FENS Forum 2024

Effects of 5-HT2AR-mGluR2-based interventions on electrophysiological biomarkers in a rat model of alcohol addiction

FENS Forum 2024

Examination of adolescent cannabinoid vapour exposure effects on behavioural predictors of addiction and alcohol use disorder features in adult male and female rats

FENS Forum 2024

Exploring the role of omega-3/omega-6 balance in long-lasting changes in microglia caused by intermittent alcohol consumption during adolescence

FENS Forum 2024

Fecal microbiota transfer reduces alcohol preference in stressed rats

FENS Forum 2024

Heavy alcohol drinking during adolescence compromises GABAergic inhibition in adult mouse dentate gyrus granule cells

FENS Forum 2024

Impaired expression of the placental angiogenic factor CD146 by prenatal alcohol exposure results in disorganized foetal brain vasculature and neurodevelopmental defects

FENS Forum 2024

Impairment of the placenta–cortex transcriptomic signature following prenatal alcohol exposure, leading to dysregulation of angiogenic pathways

FENS Forum 2024

The long-term effects of adolescent social stress on alcohol-related behaviors in adulthood

FENS Forum 2024

Microglial activation in the anterior cingulate cortex: A biological marker of early adverse events and future vulnerability to develop alcohol use disorder

FENS Forum 2024