The Course of Cognitive Performance during Inpatient Treatment in Patients with Alcohol Use Disorder with No, Mild or Major Neurocognitive Disorders.

AIMS: In patients with a history of chronic alcohol abuse, neurocognitive disorders (NCD) are not uncommon. The current study aimed to explore the course of cognitive performance, as measured by the Montreal Cognitive Assessment (MoCA), and everyday cognitive functioning, as measured by the Patient Competency Rating Scale (PCRS), in a large group of patients with alcohol use disorder (AUD) admitted to the Center of Excellence for Korsakov and Alcohol-related Cognitive Impairments. METHODS: A multiple time-series design was used, in which the MoCA was administered at three time points of assessment, and the PCRS was completed by both the patient and a clinician at two time points, all during clinical treatment. RESULTS: A total of 524 patients were included, 71 of whom were diagnosed with AUD only, 284 with AUD and mild NCD (ARCI) and 169 with AUD, major NCD and fulfilling criteria for Korsakoff's syndrome (KS). CONCLUSIONS: Cognitive performance improved for all three groups during treatment, sustained abstinence and recovery from AUD. A low memory performance on the MoCA without improvement over time was predictive for KS, while improvement on this domain did not differentiate between AUD and ARCI. Changes in overall cognitive performance and orientation in patients with KS were positively related to changes in everyday cognitive functioning.

Chronic Neurologic Effects of Alcohol.

Chronic alcohol use induces silent changes in the structure and function of the central and peripheral nervous systems that eventually result in irreversible, debilitating repercussions. Once identified, nutritional supplementation and cessation measures are critical in preventing further neurologic damage. The proposed mechanisms of neuronal injury in chronic alcohol abuse include direct toxic effects of alcohol and indirect effects, including those resulting from hepatic dysfunction, nutritional deficiencies, and neuroinflammation. Clinical manifestations include cerebellar ataxia, peripheral neuropathy and Wernicke-Korsakoff encephalopathy. Continued exploration of the pathophysiologic mechanisms may lead to the discovery of early interventions that can prevent permanent neurologic injury.

Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens.

BACKGROUND: Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens, which may contribute to the negative affective symptoms associated with ethanol withdrawal. Kappa opioid receptors have been implicated in withdrawal-induced excessive drinking and anxiety-like behaviors and are known to inhibit dopamine release in the nucleus accumbens. The effects of chronic ethanol exposure on kappa opioid receptor-mediated changes in dopamine transmission at the level of the dopamine terminal and withdrawal-related behaviors were examined. METHODS: Five weeks of chronic intermittent ethanol exposure in male C57BL/6 mice were used to examine the role of kappa opioid receptors in chronic ethanol-induced increases in ethanol intake and marble burying, a measure of anxiety/compulsive-like behavior. Drinking and marble burying were evaluated before and after chronic intermittent ethanol exposure, with and without kappa opioid receptor blockade by nor-binaltorphimine (10mg/kg i.p.). Functional alterations in kappa opioid receptors were assessed using fast scan cyclic voltammetry in brain slices containing the nucleus accumbens. RESULTS: Chronic intermittent ethanol-exposed mice showed increased ethanol drinking and marble burying compared with controls, which was attenuated with kappa opioid receptor blockade. Chronic intermittent ethanol-induced increases in behavior were replicated with kappa opioid receptor activation in naïve mice. Fast scan cyclic voltammetry revealed that chronic intermittent ethanol reduced accumbal dopamine release and increased uptake rates, promoting a hypodopaminergic state of this region. Kappa opioid receptor activation with U50,488H concentration-dependently decreased dopamine release in both groups; however, this effect was greater in chronic intermittent ethanol-treated mice, indicating kappa opioid receptor supersensitivity in this group. CONCLUSIONS: These data suggest that the chronic intermittent ethanol-induced increase in ethanol intake and anxiety/compulsive-like behaviors may be driven by greater kappa opioid receptor sensitivity and a hypodopaminergic state of the nucleus accumbens.

Moderating effect of working memory capacity on acute alcohol effects on BOLD response during inhibition and error monitoring in male heavy drinkers.

RATIONALE: While alcohol intoxication is known to increase disinhibited behavior, the degree to which disinhibition occurs appears to depend on a number of factors including executive functioning ability. However, the neural mechanisms by which individual differences in executive functioning lead to variable degrees of disinhibition remain unclear. OBJECTIVES: The aim of the current study was to examine the neural mechanisms by which individual differences in working memory (WM) capacity moderate alcohol-induced disinhibition. METHODS: Seventeen heavy-drinking males participated in a within-subjects design in which two sessions were completed: an alcohol session (.82 g/kg) and a control session. Participants completed a go/no-go task while undergoing functional magnetic resonance imaging (fMRI) after ingestion of the control or alcohol beverage. WM capacity was measured using an operation span task. RESULTS: Significant interactions of session and WM capacity emerged in contrasts examining successful response inhibition within superior temporal gyrus and unsuccessful inhibition in regions within the default mode network. In all cases, individuals with low WM capacity demonstrated a relative decrease in blood oxygen level-dependent (BOLD) response during the alcohol compared to control session, whereas the high-WM-capacity group demonstrated relative increases in BOLD response in the alcohol compared to control session. CONCLUSIONS: Low WM capacity appears to be associated with decreased neural response to signals indicating a need for behavioral control, an effect that may lead to increased difficulty with inhibiting responses and increased negative consequences from alcohol intoxication.

Diagnostic challenges in alcohol use disorder and alcoholic liver disease.

Alcohol use disorders represent a heterogeneous spectrum of clinical manifestations that have been defined by the Diagnostic and Statistical Manual of Mental Disorders-5. Excessive alcohol intake can lead to damage of various organs, including the liver. Alcoholic liver disease includes different injuries ranging from steatosis to cirrhosis and implicates a diagnostic assessment of the liver disease and of its possible complications. There is growing interest in the possible different tools for assessing previous alcohol consumption and for establishing the severity of liver injury, especially by non-invasive methods.

Psychological changes and cognitive impairments in adolescent heavy drinkers.

AIMS: Adolescence is a developmental period characterized by increased risk-taking behavior, including the initiation of alcohol and other substance use. In this brief review paper we describe psychological and cognitive constructs that are associated with heavy drinking during adolescence. These associations raise the question of causality: is alcohol somehow neurotoxic, or can we identify specific psychological and cognitive variables that serve as risk factors for the escalation of heavy drinking? METHODS: This narrative review summarizes results of recent prospective studies that focus on causal relationships between adolescents' alcohol use, and psychological changes and cognitive impairments. RESULTS: Psychological constructs such as elevated impulsivity and poor executive function are risk factors for alcohol involvement in youth. Furthermore heavy drinking during adolescence, particularly in a binge pattern, may exert neurotoxic effects and produce corresponding changes in executive function, perhaps setting the stage for the development of alcohol use disorders later on in life. CONCLUSION: Although the findings of the discussed studies shed light on the nature of the relationships between alcohol involvement and cognitive deficits, the question of cause and effect remains unanswered. The limitations of existing research and the need for well-powered prospective studies are highlighted.

Impact of alcohol use on inhibitory control (and vice versa) during adolescence and young adulthood: a review.

AIMS: Adolescence is usually the time when individuals first drink alcohol and this has been associated with relatively weak or immature inhibitory control. This review examines the changes on brain development and inhibitory function that take place during adolescence and youth as well as the relationship between inhibitory control and alcohol use at this early age. METHODS: Narrative review of the chief studies related to (a) the development of inhibitory control during adolescence, (b) the deficits in the inhibitory ability in alcohol use disorders and (c) the effects of acute alcohol intake and binge drinking on inhibitory control in adolescents and young adults. RESULTS: Inhibitory control processes are developing during adolescence and youth. Poor inhibitory functions may predispose the individual to alcohol misuse. Likewise, acute and binge alcohol drinking may impair the inhibitory control and compromise the ability to prevent or stop behaviour related to alcohol use. CONCLUSION: Poor inhibitory control can be both the cause and the consequence of excessive alcohol use. Adolescence and young adulthood may be a particularly vulnerable period due to (a) the weak or immature inhibitory functioning typical of this stage may contribute to the inability of the individual to control alcohol use and (b) alcohol consumption per se may alter or interrupt the proper development of inhibitory control leading to a reduced ability to regulate alcohol intake. Further longitudinal research is needed to evaluate the interaction between inhibitory control dysfunction and alcohol use in both situations.

Adolescence and Alcohol: a review of the literature.

Up to two thirds of adolescents consume alcohol and about a quarter engage in abusive behavior at some point. Many users begin alcohol use at young ages, and binge drinking is a dominant pattern for a proportion of youth. Because neurogenesis is inhibited by ethanol, consequences of adolescent alcohol abuse include changes in brain development and impairment of neurocognitive performance. A variety of mental and psychosocial problems are also often witnessed in alcohol abusing youth. Apart from the influence exerted by genetic and psychosocial factors, the chance of developing problematic alcohol consumption is increased by consumption in a binge drinking manner and by first contact with alcohol at a young age. Discrimination of alcohol consumption within the frames of normal adolescent behavior from problematic use is still a challenging issue. Different prevention programs provide treatment either directly to the adolescent, in the context of the school, or within the frame of the adolescent's family. Although some of these efforts have been shown to be effective in reducing alcohol misuse in youth, hardly any intervention reveals satisfactory outcomes in a long-term prospect. Successful prevention strategies would need to comprise treatment of current neuropsychological impairment as well as of comorbid mental health problems and concurrent other substance misuse.

Region-specific depression of striatal activity in Wistar rat by modest ethanol consumption over a ten-month period.

The nucleus accumbens (nAc) is the primary target for the mesolimbic dopamine system and a key brain region for the reinforcing effects displayed by drugs of abuse, including ethanol. During the transition from recreational to compulsive consumption of reinforcing drugs, however, the dorsal striatum seems to be recruited. Understanding how synaptic activity is altered in a sub-region specific manner in the striatum during the course of long-term drug consumption thus could be essential for understanding the long-lasting changes produced by addictive substances, including ethanol. Here we evaluated synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc) of single-housed Wistar rats consuming water, or water and ethanol, for up to 10 months. Even though ethanol intake was moderate, it was sufficient to decrease input/output function in response to stimulation intensity in the DLS, while recorded population spike (PS) amplitudes in the nAc were unaffected. Striatal disinhibition induced by the GABAA receptor antagonist bicuculline had a slower onset in rats that had consumed ethanol for 2 months, and was significantly depressed in slices from rats that had consumed ethanol for 4 months. Bicuculline-induced disinhibition in the nAc, on the other hand, was not significantly altered by long-term ethanol intake. Changes in PS amplitude induced by taurine or the glycine receptor antagonist strychnine were not significantly altered by ethanol in any brain region. Even though input/output function was not significantly affected by age, there was a significant decline in antagonist-induced disinhibition in brain slices from aged rats. The data presented here suggest that even modest consumption of ethanol is sufficient to alter neurotransmission in the striatum, while synaptic activity appears to be relatively well-preserved in the nAc during the course of long-term ethanol consumption.

Assessment of alcohol withdrawal in Native American patients utilizing the Clinical Institute Withdrawal Assessment of Alcohol Revised Scale.

BACKGROUND: The Clinical Institute Withdrawal Assessment of Alcohol Revised (CIWA-Ar) is a commonly used scale for assessing the severity of alcohol withdrawal syndrome in the acute setting. Despite validation of this scale in the general population, the effect of ethnicity on CIWA-Ar scoring does not appear in the literature. The purpose of our study was to investigate the validity of the CIWA-Ar scale among Native American patients evaluated for acute alcohol detoxification. METHODS: A case series of all patients seen for alcohol withdrawal at an Acute Drug and Alcohol Detoxification facility was conducted from June 1, 2011, until April 1, 2012. The CIWA-Ar scores were recorded by trained nursing staff on presentation to Triage Department and every 2 hours thereafter. At our institution, a score of 10 or greater indicates the need for inpatient hospital admission and treatment. Ethnicity was self-reported. Age, sex, blood alcohol concentration, blood pressure, and pulse were recorded on presentation and vital signs repeated every 2 hours. Patients were excluded from the study if other drug use was noted by history or initial urine drug screen. A multivariate logistic regression model was utilized to identify statistically significant variables associated with admission to the inpatient unit and treatment. The relationship of CIWA-Ar scores and ethnicity was compared using analysis of variance. RESULTS: A total of 115 whites, 45 Hispanics, and 47 Native Americans were included in the analysis. Native Americans had consistently lower CIWA-Ar scores at 0, 2, 4, and 6 hours than the other 2 ethnic groups (P = 0.002). In addition, Native Americans were admitted to the hospital less often than the other 2 groups for withdrawal (P < 0.001). CONCLUSIONS: The CIWA-Ar scale may underestimate the severity of alcohol withdrawal syndrome in certain ethnic group such as Native Americans. Further prospective studies should be undertaken to determine the validity of the CIWA-Ar scale in assessing alcohol withdrawal across different ethnic populations.

[Features of psychopharmacotherapeutic correction of alcohol dependence in the elderly].

The article is devoted to the actual in modern medicine problem as the study of the prevalence of alcohol dependence and its psyhofarmacological correction in the elderly. It is shown that elderly and old age as a result of reduction of the reserve capacity of the organism for clinical pathology becomes addictive specific psychopathological features that affect the course of disease and maintenance of preventive treatment. On the basis of empirical evidence the authors prove that at the border severity of alcohol withdrawal syndrome the drug "Cytoflavin" has a fairly pronounced psyhofarmacological activity for older people with alcohol dependence.

Adolescent brain development and underage drinking in the United States: identifying risks of alcohol use in college populations.

Alcohol use typically is initiated during adolescence, a period that coincides with critical structural and functional maturation of the brain. Brain maturation and associated improvements in decision making continue into the third decade of life, reaching a plateau within the period referred to as emerging adulthood (18-24 years). This particular period covers that of traditionally aged college students, and includes the age (21 years) when alcohol consumption becomes legal in the United States. This review highlights neurobiological evidence indicating the vulnerabilities of the emerging-adult brain to the effects of alcohol. Factors increasing the risks associated with underage alcohol use include the age group's reduced sensitivity to alcohol sedation and increased sensitivity to alcohol-related disruptions in memory. On the individual level, factors increasing those risks are a positive family history of alcoholism, which has a demonstrated effect on brain structure and function, and emerging comorbid psychiatric conditions. These vulnerabilities-of the age group, in general, as well as of particular individuals-likely contribute to excessive and unsupervised drinking in college students. Discouraging alcohol consumption until neurobiological adulthood is reached is important for minimizing alcohol-related disruptions in brain development and decision-making capacity, and for reducing the negative behavioral consequences associated with underage alcohol use.

The psycho-social rehabilitation of patients with alcohol-related brain damage in the community.

AIMS: To describe the clinical presentation, course and psycho-social outcome of patients with alcohol-related brain damage (ARBD) referred from acute general hospital inpatient settings to a newly commissioned community team. METHODS: A follow-up study of a consecutive series of 41 patients subjected to a developing, phased rehabilitation programme in community settings. RESULTS: Patients were followed for an average of 25 months. Thirty-two patients were either abstinent or categorized as 'controlled drinkers' and were placed in appropriate community settings. Acute hospital admissions were reduced by 85%. The various domains of a neuropsychiatric assessment tool, the health of the nation outcome scale-acquired brain damage, improved with the exception of concomitant mental illness and self-directed harmful behaviour. CONCLUSIONS: A community team with experience in working with younger people with cognitive impairment can provide a service for people with ARBD. Such a service is not dependent on pre-designated specialist institutions but relies on person-centred care planning, close follow-up and collaborative work with a variety of community agencies. A structured rehabilitation programme provides a framework for intervention.

KCNJ6 is associated with adult alcohol dependence and involved in gene × early life stress interactions in adolescent alcohol drinking.

Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p=0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene-environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p=0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement.

Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate.

Modulation of alcohol craving induced by challenge stimuli may predict the efficacy of new pharmacotherapies for alcoholism. We evaluated two pharmacological challenges, the α(2)-adrenergic antagonist yohimbine, which reinstates alcohol seeking in rats, and the serotonergic compound meta-chlorophenylpiperazine (mCPP), previously reported to increase alcohol craving in alcoholics. To assess the predictive validity of this approach, the approved alcoholism medication acamprosate was evaluated for its ability to modulate challenge-induced cravings. A total of 35 treatment seeking alcohol dependent inpatients in early abstinence were randomized to placebo or acamprosate (2997 mg daily). Following two weeks of medication, subjects underwent three challenge sessions with yohimbine, mCPP or saline infusion under double blind conditions, carried out in counterbalanced order, and separated by at least 5 days. Ratings of cravings and anxiety, as well as biochemical measures were obtained. In all, 25 subjects completed all three sessions and were included in the analysis. Cravings were modestly, but significantly higher following both yohimbine and mCPP challenge compared with saline infusion. The mCPP, but not yohimbine significantly increased anxiety ratings. Both challenges produced robust ACTH, cortisol and prolactin responses. There was a significant correlation between craving and the degree of alcoholism severity. Acamprosate administration did not influence craving. Both yohimbine and mCPP challenges lead to elevated alcohol craving in a clinical population of alcoholics, and these cravings correlate with alcoholism severity. Under the experimental conditions used, alcohol cravings induced by these two stimuli are not sensitive to acamprosate at clinically used doses.

Activation of σ-receptors induces binge-like drinking in Sardinian alcohol-preferring rats.

Sigma (σ) receptors have been implicated in the behavioral and motivational effects of alcohol and psychostimulants. Sigma receptor antagonists reduce the reinforcing effects of alcohol and excessive alcohol intake in both genetic (alcohol-preferring rats) and environmental (chronic alcohol-induced) models of alcoholism. The present study tested the hypothesis that pharmacological activation of σ-receptors facilitates ethanol reinforcement and induces excessive, binge-like ethanol intake. The effects of repeated subcutaneous treatment with the selective σ-receptor agonist 1,3-di-(2-tolyl)guanidine (DTG; 15 mg/kg, twice a day for 7 days) on operant ethanol (10%) self-administration were studied in Sardinian alcohol-preferring (sP) rats. To confirm that the effect of DTG was mediated by σ-receptors, the effects of pretreatment with the selective σ-receptor antagonist BD-1063 (7 mg/kg, subcutaneously) were determined. To assess the specificity of action, the effects of DTG on the self-administration of equally reinforcing solutions of saccharin or sucrose were also determined. Finally, gene expression of opioid receptors in brain areas implicated in ethanol reinforcement was analyzed in ethanol-naive sP rats treated acutely or repeatedly with DTG, because of the well-established role of the opioid system in alcohol reinforcement and addiction. Repeatedly administered DTG progressively and dramatically increased ethanol self-administration in sP rats and increased blood alcohol levels, which reached mean values close to 100 mg% in 1 h drinking sessions. Repeated DTG treatment also increased the rats' motivation to work for alcohol under a progressive-ratio schedule of reinforcement. BD-1063 prevented the effects of DTG, confirming that σ-receptors mediate the effects of DTG. Repeated DTG treatment also increased the self-administration of the non-drug reinforcers saccharin and sucrose. Naive sP rats repeatedly treated with DTG showed increased mRNA expression of µ- and δ-opioid receptors in the ventral tegmental area. These results suggest a key facilitatory role for σ-receptors in the reinforcing effects of alcohol and identify a potential mechanism that contributes to binge-like and excessive drinking.

Stress and alcohol cues exert conjoint effects on go and stop signal responding in male problem drinkers.

Stress, cues, and pharmacological priming are linked with relapse to addictive behavior. Increased salience and decreased inhibitory control are thought to mediate the effects of relapse-related stimuli. However, the functional relationship between these two processes is unclear. To address this issue, a modified Stop Signal Task was employed, which used Alcohol, Neutral, and Non-Words as Go stimuli, and lexical decision as the Go response. Subjects were 38 male problem drinkers (mean Alcohol Dependence Scale (ADS) score: 18.0). Uncontrollable noise (∼ 10 min at 110 dB) was the stressor; nonalcoholic placebo beer (P-Beer) was the cue manipulation, and alcohol (0.7 g/kg), the pharmacological prime. Half the sample received alcohol, and half P-Beer. Stress and beverage (test drink vs soft drink) were manipulated within subjects on two sessions, with half the sample receiving active manipulations together and half receiving them separately. Go response time (RT) and Stop Signal RT (SSRT) were slower to Alcohol than Neutral words. Stress augmented this bias. Alcohol and P-Beer impaired overall SSRT. Stress impaired neither overall SSRT nor Go RT. SSRT to Neutral words and Non-Words correlated inversely with Go RT to Alcohol and Neutral words, and Non-Words. ADS correlated directly with SSRT to Alcohol words. A resource allocation account was proposed, whereby diversion of limited resources to salient cues effectively yoked otherwise independent Go and Stop processes. Disturbances of prefrontal norepinephrine and dopamine were cited as possibly accounting for these effects. Treatments that optimize prefrontal catecholamine transmission may deter relapse by reducing disinhibitory effects of salient eliciting stimuli.

Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence.

Studies over the last decade demonstrate that adolescence is a brain maturation period from childhood to adulthood. Plastic and dynamic processes drive adolescent brain development, creating flexibility that allows the brain to refine itself, specialize, and sharpen its functions for specific demands. Maturing connections enable increased communication among brain regions, allowing greater integration and complexity. Compelling evidence has shown that the developing brain is vulnerable to the damaging effects of ethanol. It is possible to infer, therefore, that alcohol exposure during the critical adolescent developmental stages could disrupt the brain plasticity and maturation processes, resulting in behavioral and cognitive deficits. Recent neuroimaging studies have provided evidence of the impact of human adolescent drinking in brain structure and functions. Findings in experimental animals have also given new insight into the potential mechanisms of the toxic effects of ethanol on both adolescent brain maturation and the short- and long-term cognitive consequences of adolescent drinking. Adolescence is also characterized by the rapid maturation of brain systems mediating reward and by changes in the secretion of stress-related hormones, events that might participate in the increasing in anxiety and the initiation pattern of alcohol and drug consumption. Studies in human adolescents demonstrate that drinking at early ages can enhance the likelihood of developing alcohol-related problems. Experimental evidence suggests that early exposure to alcohol sensitizes the neurocircuitry of addiction and affects chromatin remodeling, events that could induce abnormal plasticity in reward-related learning processes that contribute to adolescents' vulnerability to drug addiction. In this article, we review the potential mechanisms by which ethanol impacts brain development and lead to brain impairments and cognitive and behavioral dysfunctions as well as the neurobiological and neurochemical processes underlying the adolescent-specific vulnerability to drug addiction.