Medications for alcohol use disorders: An overview.

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.

The conception of the ABCD study: From substance use to a broad NIH collaboration.

Adolescence is a time of dramatic changes in brain structure and function, and the adolescent brain is highly susceptible to being altered by experiences like substance use. However, there is much we have yet to learn about how these experiences influence brain development, how they promote or interfere with later health outcomes, or even what healthy brain development looks like. A large longitudinal study beginning in early adolescence could help us understand the normal variability in adolescent brain and cognitive development and tease apart the many factors that influence it. Recent advances in neuroimaging, informatics, and genetics technologies have made it feasible to conduct a study of sufficient size and scope to answer many outstanding questions. At the same time, several Institutes across the NIH recognized the value of collaborating in such a project because of its ability to address the role of biological, environmental, and behavioral factors like gender, pubertal hormones, sports participation, and social/economic disparities on brain development as well as their association with the emergence and progression of substance use and mental illness including suicide risk. Thus, the Adolescent Brain Cognitive Development study was created to answer the most pressing public health questions of our day.

Genetic studies of alcohol dependence in the context of the addiction cycle.

Family, twin and adoption studies demonstrate clearly that alcohol dependence and alcohol use disorders are phenotypically complex and heritable. The heritability of alcohol use disorders is estimated at approximately 50-60% of the total phenotypic variability. Vulnerability to alcohol use disorders can be due to multiple genetic or environmental factors or their interaction which gives rise to extensive and daunting heterogeneity. This heterogeneity makes it a significant challenge in mapping and identifying the specific genes that influence alcohol use disorders. Genetic linkage and (candidate gene) association studies have been used now for decades to map and characterize genomic loci and genes that underlie the genetic vulnerability to alcohol use disorders. These approaches have been moderately successful in identifying several genes that contribute to the complexity of alcohol use disorders. Recently, genome-wide association studies have become one of the major tools for identifying genes for alcohol use disorders by examining correlations between millions of common single-nucleotide polymorphisms with diagnosis status. Genome-wide association studies are just beginning to uncover novel biology; however, the functional significance of results remains a matter of extensive debate and uncertainty. In this review, we present a select group of genome-wide association studies of alcohol dependence, as one example of a way to generate functional hypotheses, within the addiction cycle framework. This analysis may provide novel directions for validating the functional significance of alcohol dependence candidate genes. This article is part of the Special Issue entitled "Alcoholism".

Brain mechanisms of Change in Addictions Treatment: Models, Methods, and Emerging Findings.

Increased understanding of "how" and "for whom" treatment works at the level of the brain has potential to transform addictions treatment through the development of innovative neuroscience-informed interventions. The 2015 Science of Change meeting bridged the fields of neuroscience and psychotherapy research to identify brain mechanisms of behavior change that are "common" across therapies, and "specific" to distinct behavioral interventions. Conceptual models of brain mechanisms underlying effects of Cognitive Behavioral Therapy, mindfulness interventions, and Motivational Interviewing were discussed. Presentations covered methods for integrating neuroimaging into psychotherapy research, and novel analytic approaches. Effects of heavy substance use on the brain, and recovery of brain functioning with sustained abstinence, which may be facilitated by cognitive training, were reviewed. Neuroimaging provides powerful tools for determining brain mechanisms underlying psychotherapy and medication effects, predicting and monitoring outcomes, developing novel interventions that target specific brain circuits, and identifying for whom an intervention will be effective.

Brain pathways to recovery from alcohol dependence.

This article highlights the research presentations at the satellite symposium on "Brain Pathways to Recovery from Alcohol Dependence" held at the 2013 Society for Neuroscience Annual Meeting. The purpose of this symposium was to provide an up to date overview of research efforts focusing on understanding brain mechanisms that contribute to recovery from alcohol dependence. A panel of scientists from the alcohol and addiction research field presented their insights and perspectives on brain mechanisms that may underlie both recovery and lack of recovery from alcohol dependence. The four sessions of the symposium encompassed multilevel studies exploring mechanisms underlying relapse and craving associated with sustained alcohol abstinence, cognitive function deficit and recovery, and translational studies on preventing relapse and promoting recovery. Gaps in our knowledge and research opportunities were also discussed.

Perspectives on the neuroscience of alcohol from the National Institute on Alcohol Abuse and Alcoholism.

Mounting evidence over the last 40 years clearly indicates that alcoholism (alcohol dependence) is a disorder of the brain. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) has taken significant steps to advance research into the neuroscience of alcohol. The Division of Neuroscience and Behavior (DNB) was formed within NIAAA in 2002 to oversee, fund, and direct all research areas that examine the effects of alcohol on the brain, the genetic underpinnings of alcohol dependence, the neuroadaptations resulting from excessive alcohol consumption, advanced behavioral models of the various stages of the addiction cycle, and preclinical medications development. This research portfolio has produced important discoveries in the etiology, treatment, and prevention of alcohol abuse and dependence. Several of these salient discoveries are highlighted and future areas of neuroscience research on alcohol are presented.

New insights on neurobiological mechanisms underlying alcohol addiction.

Alcohol dependence/addiction is mediated by complex neural mechanisms that involve multiple brain circuits and neuroadaptive changes in a variety of neurotransmitter and neuropeptide systems. Although recent studies have provided substantial information on the neurobiological mechanisms that drive alcohol drinking behavior, significant challenges remain in understanding how alcohol-induced neuroadaptations occur and how different neurocircuits and pathways cross-talk. This review article highlights recent progress in understanding neural mechanisms of alcohol addiction from the perspectives of the development and maintenance of alcohol dependence. It provides insights on cross talks of different mechanisms and reviews the latest studies on metaplasticity, structural plasticity, interface of reward and stress pathways, and cross-talk of different neural signaling systems involved in binge-like drinking and alcohol dependence.

Using genetically engineered animal models in the postgenomic era to understand gene function in alcoholism.

Over the last 50 years, researchers have made substantial progress in identifying genetic variations that underlie the complex phenotype of alcoholism. Not much is known, however, about how this genetic variation translates into altered biological function. Genetic animal models recapitulating specific characteristics of the human condition have helped elucidate gene function and the genetic basis of disease. In particular, major advances have come from the ability to manipulate genes through a variety of genetic technologies that provide an unprecedented capacity to determine gene function in the living organism and in alcohol-related behaviors. Even newer genetic-engineering technologies have given researchers the ability to control when and where a specific gene or mutation is activated or deleted, allowing investigators to narrow the role of the gene's function to circumscribed neural pathways and across development. These technologies are important for all areas of neuroscience, and several public and private initiatives are making a new generation of genetic-engineering tools available to the scientific community at large. Finally, high-throughput "next-generation sequencing" technologies are set to rapidly increase knowledge of the genome, epigenome, and transcriptome, which, combined with genetically engineered mouse mutants, will enhance insight into biological function. All of these resources will provide deeper insight into the genetic basis of alcoholism.

Medications development to treat alcohol dependence: a vision for the next decade.

More than 76 million people world-wide are estimated to have diagnosable alcohol use disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The US Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholism's (NIAAA's) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, the NIAAA Medications Development Team has identified three fundamental long-range goals: (1) to make the drug development process more efficient; (2) to identify more efficacious medications, personalize treatment approaches, or both; and (3) to facilitate the implementation and adaptation of medications in real-world treatment settings. These goals will be carried out through seven key objectives. This paper describes those objectives in terms of rationale and strategy. Successful implementation of these objectives will result in the development of more efficacious and safe medications, provide a greater selection of therapy options and ultimately lessen the impact of this devastating disorder.

[Parasitological, immunohistochemical and histopathological study for Leishmania chagasi detection in splenic tissues of dogs with visceral leishmaniasis]. / Exames parasitológicos, imunoistoquímicos e histopatológicos para detecção de Leishania chagasi em tecidos esplênicos de cães com leishmaniose visceral.

The purpose of this work was a Canine Visceral Leishmaniasis--CVL study by parasitological direct examination of Leishmania (L.) chagasi (imprinting and histological), immunohistochemical test and histopathological analysis using spleen tissues from 34 dogs euthanized by the Zoonotic Disease Control Centre from Ilha Solteira, SP, Brazil. According to the clinical signs, the dogs were divided in three groups: asymptomatics (8 dogs), oligosymptomatics (17 dogs) and symptomatics (9 dogs). After the accomplishment of all diagnostic tests, 22 dogs were considered positives (64.7%) and 12 (35.3%) were negatives to CVL. From these positive dogs, 1/22 (4.5%) was asymptomatic, 12/22(54.5%) were oligosymptomatics and 8/22 (40.1%) were symptomatics. The histopathological study in spleen tissues from positive, especially symptomatic dogs, showed a diffuse chronic inflammation with thickness of capsular and trabecular regions and there was extensive morphologic alteration of the red and white pulp by the presence of abundant macrophages full with amastigotes, the granulomatous inflammatory reaction and haemorrhagic areas. The data of this work from histopathologic examination and direct microscopic visualization of L. (L.) chagasi showed that the spleen was an useful organ to collect sample tissues for CVL diagnosis. The immunostaining detected the highest number of positive dogs and were considered an important and conclusive method to be used in addition to parasitological methods for CVL, particularly in asymptomatic or oligosymptomatic dogs.

Eimeria spp. in Brazilian water buffalo.

Eimeria species are frequently found in water buffalo (Bubalus bubalis) in Brazil. Here, we report those Eimeria spp. that infect buffalos during their first year of life. Fresh fecal samples were examined from 2 groups (1 group/yr for 2 yr, 2000-2002), each with 18 water buffalo calves (both sexes), from birth through 12 mo of age, in Selvíria, MS, Brazil. Five oocyst morphotypes were observed, i.e., Eimeria ellipsoidalis and Eimeria zuernii, both previously described from water buffalo, and 3 other morphotypes consistent with descriptions of known Eimeria spp. from Artiodactyla hosts, but originally described from other genera than those in which we found them (referred to here as Eimeria species 1-3). Our results showed that buffalo calves started shedding oocysts in their feces between 6-29 days of age, with the highest concentration ranging from 188-292 oocysts/g of feces. The 3 unnamed oocyst morphotypes in the calf feces resembled E. auburnensis (Eimeria sp. 3), E. cylindrica (Eimeria sp. 1), and E. subspherica (Eimeria sp. 2). The most prevalent species were Eimeria sp. 1 and E. ellipsoidalis, which dominated in the youngest animals (6 to 133 days old). Eimeria zuernii oocysts, in contrast, were found only in low numbers in the feces of older calves (208 to 283 days old). Calves were infected more frequently during the rainy season (September to January) in both years, but cows were negative for Eimeria spp., whenever feces were collected (spring, winter, autumn, or summer seasons).

Structural and Thermodynamic Analysis of the First Mononuclear Aqueous Aluminum Citrate Complex Using DFT Calculations.

Structural and thermodynamic properties of the mononuclear Al/citrate complexes have been theoretically investigated aiming to understand the coordination mechanism at an atomic level. GGA-DFT/PCM calculations have been performed for the different conformations and tautomers arising from the Al(3+) and citric acid (H3L) interaction in aqueous solution. The Gibbs reaction energies were estimated based on the reaction of the trigonal planar Al(OH)3 and H3L to form different Al-citrate complexes. The estimated Gibbs free reaction energies for the [AlL], [AlHL](+), and [Al(OH)L](-) species are in good agreement with the experimental values. In these species, the Al(3+) center is coordinated by two carboxylic and the tertiary hydroxyl groups of the citrate. Conversely to what has been proposed based on the experiments, the present theoretical calculations indicate that the citric acid hydroxyl group remains protonated upon the coordination of Al(3+). In fact, our model turns out to be more consistent with the relative pKa values of citrate protonation groups and with the hydrolysis constant of the H2O bound to Al(3+) leading to better agreement with the available experimental data.

DFT study of the V(IV)/V(V) oxidation mechanism in the presence of N-hydroxyacetamide.

The oxidation mechanism of V(IV)/V(V) in the presence of N-hydroxyacetamide (acetohydroxamic acid, HL) in aqueous solution has been investigated using density functional theory (DFT) calculations aiming to contribute to the understanding of this process at a molecular level. The mechanism proposed involves formation of the *OH, *OOH, H2O2 radicals and complexes formed from the interaction of these species with VOL2 complex. The Gibbs free energy of each step of the mechanism has been evaluated. The solvation energy has been estimated by means of united atoms Hartree-Fock/polarizable continuum method (UAHF/PCM). The Gibbs free energy of the global reaction of the V(IV)/V(V) oxidation has been estimated and compared with the available experimental equilibrium constant. The difference between the calculated and experimental estimates for the reaction energy of the global equation is about 1.5 kcal mol(-1). The thermodynamic profile of the reaction mechanism has been provided and discussed in terms of the possible intermediates. The influence of the ligand and the reaction rate in terms of the steady-state approximation has been briefly discussed.

Alcohol-induced neurodegeneration: when, where and why?

This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fulton Crews presented at the 2003 Research Society on Alcoholism meeting. The purpose of the symposium was to examine recent findings on when alcohol induced brain damage occurs, e.g., during intoxication and/or during alcohol withdrawal. Further studies investigate specific brain regions (where) and the mechanisms (why) of alcoholic neurodegeneration. The presentations were (1) Characterization of Synaptic Loss in Cerebella of Mature and Senescent Rats after Lengthy Chronic Ethanol Consumption, (2) Ethanol Withdrawal Both Causes Neurotoxicity and Inhibits Neuronal Recovery Processes in Rat Organotypic Hippocampal Cultures, (3) Binge Drinking-Induced Brain Damage: Genetic and Age Related Effects, (4) Binge Ethanol-Induced Brain Damage: Involvement of Edema, Arachidonic Acid and Tissue Necrosis Factor alpha (TNFalpha), and (5) Cyclic AMP Cascade, Stem Cells and Ethanol. Taken together these studies suggest that alcoholic neurodegeneration occurs through multiple mechanisms and in multiple brain regions both during intoxication and withdrawal.