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International Review of Neurobiology 2021Alcohol use disorder is a chronic debilitated condition adversely affecting the lives of millions of individuals throughout the modern world. Individuals suffering from...
Alcohol use disorder is a chronic debilitated condition adversely affecting the lives of millions of individuals throughout the modern world. Individuals suffering from an alcohol use disorder diagnosis frequently have serious cooccurring conditions, which often further exacerbates problematic drinking behavior. Comprehending the biochemical processes underlying the progression and perpetuation of disease is essential for mitigating maladaptive behavior in order to restore both physiological and psychological health. The range of cellular and biological systems contributing to, and affected by, alcohol use disorder and other comorbid disorders necessitates a fundamental grasp of intricate functional relationships that govern molecular biology. Epigenetic factors are recognized as essential mediators of cellular behavior, orchestrating a symphony of gene expression changes within multicellular environments that are ultimately responsible for directing human behavior. Understanding the epigenetic and transcriptional regulatory mechanisms involved in the pathogenesis of disease is important for improving available pharmacotherapies and reducing the incidence of alcohol abuse and cooccurring conditions.
Topics: Alcoholism; Behavior, Addictive; Epigenesis, Genetic; Gene Expression Regulation; Humans
PubMed: 33461665
DOI: 10.1016/bs.irn.2020.08.006 -
International Journal of Molecular... Nov 2022Recreational use of alcohol is a social norm in many communities worldwide. Alcohol use in moderation brings pleasure and may protect the cardiovascular system. However,... (Review)
Review
Recreational use of alcohol is a social norm in many communities worldwide. Alcohol use in moderation brings pleasure and may protect the cardiovascular system. However, excessive alcohol consumption or alcohol abuse are detrimental to one's health. Three million deaths due to excessive alcohol consumption were reported by the World Health Organization. Emerging evidence also revealed the danger of moderate consumption, which includes the increased risk to cancer. Alcohol abuse and periods of withdrawal have been linked to depression and anxiety. Here, we present the effects of alcohol consumption (acute and chronic) on important brain structures-the frontal lobe, the temporal lobe, the limbic system, and the cerebellum. Apart from this, we also present the link between alcohol abuse and withdrawal and mood disorders in this review, thus drawing a link to oxidative stress. In addition, we also discuss the positive impacts of some pharmacotherapies used. Due to the ever-rising demands of life, the cycle between alcohol abuse, withdrawal, and mood disorders may be a never-ending cycle of destruction. Hence, through this review, we hope that we can emphasise the importance and urgency of managing this issue with the appropriate approaches.
Topics: Humans; Alcoholism; Substance Withdrawal Syndrome; Mood Disorders; Alcohol Drinking; Anxiety Disorders
PubMed: 36499240
DOI: 10.3390/ijms232314912 -
Pharmacology, Biochemistry, and Behavior Feb 2019Alcohol use disorder (AUD) is a widespread disease with limited treatment options. Targeting the neuroimmune system is a new avenue for developing or repurposing... (Review)
Review
Alcohol use disorder (AUD) is a widespread disease with limited treatment options. Targeting the neuroimmune system is a new avenue for developing or repurposing effective pharmacotherapies. Alcohol modulates innate immune signaling in different cell types in the brain by altering gene expression and the molecular pathways that regulate neuroinflammation. Chronic alcohol abuse may cause an imbalance in neuroimmune function, resulting in prolonged perturbations in brain function. Likewise, manipulating the neuroimmune system may change alcohol-related behaviors. Psychiatric disorders that are comorbid with AUD, such as post-traumatic stress disorder, major depressive disorder, and other substance use disorders, may also have underlying neuroimmune mechanisms; current evidence suggests that convergent immune pathways may be involved in AUD and in these comorbid disorders. In this review, we provide an overview of major neuroimmune cell-types and pathways involved in mediating alcohol behaviors, discuss potential mechanisms of alcohol-induced neuroimmune activation, and present recent clinical evidence for candidate immune-related drugs to treat AUD.
Topics: Alcoholism; Animals; Brain; Comorbidity; Depressive Disorder, Major; Humans; Immunity, Innate; Immunomodulation; Mice; Neuroimmunomodulation; Rats; Stress Disorders, Post-Traumatic
PubMed: 30590091
DOI: 10.1016/j.pbb.2018.12.007 -
Pharmacology & Therapeutics May 2018Patients who suffer from alcohol use disorders (AUDs) usually go through various socio-behavioral and pathophysiological changes that take place in the brain and other... (Review)
Review
Patients who suffer from alcohol use disorders (AUDs) usually go through various socio-behavioral and pathophysiological changes that take place in the brain and other organs. Recently, consumption of unhealthy food and excess alcohol along with a sedentary lifestyle has become a norm in both developed and developing countries. Despite the beneficial effects of moderate alcohol consumption, chronic and/or excessive alcohol intake is reported to negatively affect the brain, liver and other organs, resulting in cell death, organ damage/failure and death. The most effective therapy for alcoholism and alcohol related comorbidities is alcohol abstinence, however, chronic alcoholic patients cannot stop drinking alcohol. Therefore, targeted therapies are urgently needed to treat such populations. Patients who suffer from alcoholism and/or alcohol abuse experience harmful effects and changes that occur in the brain and other organs. Upon stopping alcohol consumption, alcoholic patients experience acute withdrawal symptoms followed by a protracted abstinence syndrome resulting in the risk of relapse to heavy drinking. For the past few decades, several drugs have been available for the treatment of AUDs. These drugs include medications to reduce or stop severe alcohol withdrawal symptoms during alcohol detoxification as well as recovery medications to reduce alcohol craving and support abstinence. However, there is no drug that completely antagonizes the adverse effects of excessive amounts of alcohol. This review summarizes the drugs which are available and approved by the FDA and their mechanisms of action as well as the medications that are under various phases of preclinical and clinical trials. In addition, the repurposing of the FDA approved drugs, such as anticonvulsants, antipsychotics, antidepressants and other medications, to prevent alcoholism and treat AUDs and their potential target mechanisms are summarized.
Topics: Alcoholism; Animals; Drug Approval; Drug Repositioning; Humans; Signal Transduction; United States; United States Food and Drug Administration
PubMed: 29191394
DOI: 10.1016/j.pharmthera.2017.11.007 -
Molecular Psychiatry Nov 2022Positive effects of alcohol drinking such as anxiolysis and euphoria appear to be a crucial factor in the initiation and maintenance of alcohol use disorder (AUD)....
Positive effects of alcohol drinking such as anxiolysis and euphoria appear to be a crucial factor in the initiation and maintenance of alcohol use disorder (AUD). However, the mechanisms that lead from chromatin reorganization to transcriptomic changes after acute ethanol exposure remain unknown. Here, we used Assay for Transposase-Accessible Chromatin followed by high throughput sequencing (ATAC-seq) and RNA-seq to investigate epigenomic and transcriptomic changes that underlie anxiolytic effects of acute ethanol using an animal model. Analysis of ATAC-seq data revealed an overall open or permissive chromatin state that was associated with transcriptomic changes in the amygdala after acute ethanol exposure. We identified a candidate gene, Hif3a (Hypoxia-inducible factor 3, alpha subunit), that had 'open' chromatin regions (ATAC-seq peaks), associated with significantly increased active epigenetic histone acetylation marks and decreased DNA methylation at these regions. The mRNA levels of Hif3a were increased by acute ethanol exposure, but decreased in the amygdala during withdrawal after chronic ethanol exposure. Knockdown of Hif3a expression in the central nucleus of amygdala attenuated acute ethanol-induced increases in Hif3a mRNA levels and blocked anxiolysis in rats. These data indicate that chromatin accessibility and transcriptomic signatures in the amygdala after acute ethanol exposure underlie anxiolysis and possibly prime the chromatin for the development of AUD.
Topics: Animals; Rats; Epigenesis, Genetic; Ethanol; Chromatin; Gene Expression Profiling; Alcoholism; RNA, Messenger; Transcription Factors
PubMed: 36089615
DOI: 10.1038/s41380-022-01732-2 -
Alcohol Research : Current Reviews 2022This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as... (Review)
Review
This article is part of a Festschrift commemorating the 50th anniversary of the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Established in 1970, first as part of the National Institute of Mental Health and later as an independent institute of the National Institutes of Health, NIAAA today is the world's largest funding agency for alcohol research. In addition to its own intramural research program, NIAAA supports the entire spectrum of innovative basic, translational, and clinical research to advance the diagnosis, prevention, and treatment of alcohol use disorder and alcohol-related problems. To celebrate the anniversary, NIAAA hosted a 2-day symposium, "Alcohol Across the Lifespan: 50 Years of Evidence-Based Diagnosis, Prevention, and Treatment Research," devoted to key topics within the field of alcohol research. This article is based on Dr. Tapert's presentation at the event. NIAAA Director George F. Koob, Ph.D., serves as editor of the Festschrift.
Topics: Adolescent; Alcohol Drinking; Alcohol-Related Disorders; Alcoholism; Brain; Humans; National Institute on Alcohol Abuse and Alcoholism (U.S.); United States
PubMed: 35465194
DOI: 10.35946/arcr.v42.1.07 -
Cellular and Molecular Life Sciences :... Dec 2017Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light... (Review)
Review
Alcoholic beverages are widely consumed, resulting in a staggering economic cost in different social and cultural settings. Types of alcohol consumption vary from light occasional to heavy, binge drinking, and chronic alcohol abuse at all ages. In general, heavy alcohol consumption is widely recognized as a major epidemiological risk factor for chronic diseases and is detrimental to many organs and tissues, including bones. Indeed, recent findings demonstrate that alcohol has a dose-dependent toxic effect in promoting imbalanced bone remodeling. This imbalance eventually results in osteopenia, an established risk factor for osteoporosis. Decreased bone mass and strength are major hallmarks of osteopenia, which is predominantly attributed not only to inhibition of bone synthesis but also to increased bone resorption through direct and indirect pathways. In this review, we present knowledge to elucidate the epidemiology, potential pathogenesis, and major molecular mechanisms and cellular effects that underlie alcoholism-induced bone loss in osteopenia. Novel therapeutic targets for correcting alcohol-induced osteopenia are also reviewed, such as modulation of proinflammatory cytokines and Wnt and mTOR signaling and the application of new drugs.
Topics: Alcohol Drinking; Alcoholism; Animals; Bone Diseases, Metabolic; Bone Resorption; Ethanol; Humans; Osteoporosis; Risk Factors
PubMed: 28674727
DOI: 10.1007/s00018-017-2585-y -
Journal of Ethnicity in Substance Abuse 2022The study explored associations among childhood abuse, post-traumatic stress symptoms (PTSS), and alcohol misuse in a sample of low-income African-American women...
The study explored associations among childhood abuse, post-traumatic stress symptoms (PTSS), and alcohol misuse in a sample of low-income African-American women ( = 172). Using bootstrapping techniques, a mediation effect was found of childhood physical and emotional abuse on alcohol misuse via PTSS symptom severity, avoidance, and hyperarousal, as well as for childhood sexual abuse on alcohol misuse via PTSS symptom severity and hyperarousal. Our results suggest that PTSS indicators, particularly symptom severity and hyperarousal, may be important mechanisms underlying the association of experiences of abuse during childhood and alcohol misuse in adulthood.
Topics: Adult; Black or African American; Alcoholism; Child; Child Abuse; Female; Humans; Stress Disorders, Post-Traumatic; United States
PubMed: 32065558
DOI: 10.1080/15332640.2020.1725707 -
Neuroscience Letters Aug 2015Alcohol use and alcohol addiction represent dysfunctional brain circuits resulting from neuroadaptive changes during protracted alcohol exposure and its withdrawal.... (Review)
Review
Alcohol use and alcohol addiction represent dysfunctional brain circuits resulting from neuroadaptive changes during protracted alcohol exposure and its withdrawal. Alcohol exerts a potent effect on synaptic plasticity and dendritic spine formation in specific brain regions, providing a neuroanatomical substrate for the pathophysiology of alcoholism. Epigenetics has recently emerged as a critical regulator of gene expression and synaptic plasticity-related events in the brain. Alcohol exposure and withdrawal induce changes in crucial epigenetic processes in the emotional brain circuitry (amygdala) that may be relevant to the negative affective state defined as the "dark side" of addiction. Here, we review the literature concerning synaptic plasticity and epigenetics, with a particular focus on molecular events related to dendritic remodeling during alcohol abuse and alcoholism. Targeting epigenetic processes that modulate synaptic plasticity may yield novel treatments for alcoholism.
Topics: Alcoholism; Cognition; Dendritic Spines; Epigenesis, Genetic; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Humans; Male; Neuronal Plasticity; Receptors, Opioid, kappa; Synapses
PubMed: 25623036
DOI: 10.1016/j.neulet.2015.01.051 -
Biological Psychiatry Feb 2023Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of...
BACKGROUND
Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood.
METHODS
We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation-based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795).
RESULTS
Composite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation-based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts.
CONCLUSIONS
A methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.
Topics: Humans; Alcoholism; Aging, Premature; Alcohol Drinking; DNA Methylation; Epigenesis, Genetic
PubMed: 36182531
DOI: 10.1016/j.biopsych.2022.06.036