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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., (© The Author(s) 2020. Medical Council on Alcohol and Oxford University Press.)

Studies with human subjects indicate that ethanol exposure during fetal development causes long-lasting alterations in motor coordination that are, in part, a consequence of cerebellar damage. Studies with rats exposed to ethanol during the neonatal brain growth spurt have consistently recapitulated these deficits. However, studies with mice have yielded mixed results. We hypothesized that the use of highly sensitive motor function tests, such as the Catwalk test, would reliably detect motor function deficits in mice developmentally exposed to ethanol. Venus-vesicular GABA transporter transgenic mice were ethanol exposed during postnatal days 4-9 using vapor inhalation chambers and then subjected to the Catwalk test during adolescence. Catwalk data were rigorously analyzed using an innovative multistep statistical approach. For comparison, motor coordination and strength were assessed with the triple horizontal bar and rotarod tests. Unexpectedly, we found that out of 186 parameters analyzed in the Catwalk test, only one was affected by ethanol exposure (i.e., reduced coupling between left front paw and the right hind paw). In the triple horizontal bar test, ethanol-exposed mice were able to hold to the bars for less time than controls. Surprisingly, ethanol-exposed mice performed better in the rotarod test than controls. These data indicate that neonatal ethanol exposure of mice causes mixed effects on motor function during adolescence. The Catwalk test suggests that gait is generally preserved in these mice, whereas the triple horizontal bar test revealed deficits on motor strength and the rotarod test an increase in motor coordination., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Ethanol consumption induces neurological disorders including cognitive dysfunction. Oxidative damage is considered a likely cause of cognitive deficits. We aimed to investigate the effects of rosmarinic acid (RA) in different doses for 30 days on chronic ethanol-induced cognitive dysfunction using the passive avoidance learning (PAL) and memory task in comparison with donepezil, a reference drug. We also evaluated the levels of superoxide dismutase (SOD), catalase (CAT), and lipid peroxidation in hippocampus as possible mechanisms., Methods: Memory impairment was induced by 15% w/v ethanol (2 g/kg, i.g.) administration for 30 days. RA (8, 16, and 32 mg/kg, i.g.) or donepezil (2 mg/kg, i.g.) was administered 30 minutes before ethanol. The acquisition trial was done 1 hour after the last administration of RA and donepezil. At the end, animals were weighed and hippocami were isolated for analyzing of oxidant/antioxidant markers., Results: Ethanol caused cognition deficits in the PAL and memory task. While RA 16 and 32 mg/kg improved cognition in control rats, it prevented learning and memory deficits of alcoholic groups. RA 8 mg/kg did not influence cognitive function in both control and alcoholic rats. RA 32 mg/kg had comparable effects with donepezil in prevention of acquisition and retention memory impairment. The higher doses of RA not only prevented increased lipid peroxidation and nitrite content but also decreased SOD, CAT, GSH, and FRAP levels in alcoholic groups and exerted antioxidant effects in non-alcoholic rats., Discussion: We showed that RA administration dose-dependently prevented cognitive impairment induced by chronic ethanol in PAL and memory and disturbed oxidant/antioxidant status as a possible mechanism. The antioxidant, anticholinesterase, and neuroprotective properties of RA may be involved in the observed effects. Therefore, RA represents a potential therapeutic option against chronic ethanol-induced amnesia which deserves consideration and further examination.

Post-traumatic stress disorder (PTSD) and alcohol-use disorder (AUD) are highly comorbid in humans. Although we have some understanding of the structural and functional brain changes that define each of these disorders, and how those changes contribute to the behavioral symptoms that define them, little is known about the neurobiology of comorbid PTSD and AUD, which may be due in part to a scarcity of adequate animal models for examining this research question. The goal of this review is to summarize the current state-of-the-science on comorbid PTSD and AUD. We summarize epidemiological data documenting the prevalence of this comorbidity, review what is known about the potential neurobiological basis for the frequent co-occurrence of PTSD and AUD and discuss successes and failures of past and current treatment strategies. We also review animal models that aim to examine comorbid PTSD and AUD, highlighting where the models parallel the human condition, and we discuss the strengths and weaknesses of each model. We conclude by discussing key gaps in our knowledge and strategies for addressing them: in particular, we (1) highlight the need for better animal models of the comorbid condition and better clinical trial design, (2) emphasize the need for examination of subpopulation effects and individual differences and (3) urge cross-talk between basic and clinical researchers that is reflected in collaborative work with forward and reverse translational impact., (© 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Alcohol consumption triggers a neuroinflammatory response which, if prolonged, can lead to substantial volume loss in both gray and white matter. This brain injury is associated with characteristic cognitive deficits, and, in extreme cases, with dementia. Even mild cognitive impairment creates a significant hurdle for alcohol rehabilitation, because the domains that are affected tend to be those important for sustaining abstinence. Thus, cognitive decline induced by alcohol contributes to the persistence of alcoholism. Here, I present converging data from animal and clinical studies that show how alcohol affects the brain and behavior. Although there is currently no targeted treatment for overcoming alcohol-induced cognitive decline, emerging evidence suggests that physical activity is both protective and restorative. This is a potential avenue for future programs targeted at treating alcohol abuse.

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., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

The authors evaluated all available evidence on the use of propofol as an adjuvant for the treatment of resistant alcohol withdrawal syndrome (AWS) in comparison to other therapies. A comprehensive PubMed search (1966-December 2015) was conducted using the search terms propofol, alcohol withdrawal, and drug therapy. Articles were cross-referenced for other citations. Clinical studies, case series, and case reports published in the English language assessing the use of propofol in adult patients for treatment of AWS were reviewed for inclusion. Propofol is a sedative-hypnotic that exerts its actions through agonism of GABAA receptors at a different binding site than benzodiazepines and reduces glutamatergic activity through N-methyl-d-aspartase (NMDA) receptor blockade. Dosages from 5 to 100 μg/kg/minute reduced AWS symptoms with frequent development of hypotension and requirement for mechanical ventilation. Patients on propofol often experienced longer durations of mechanical ventilation and length of stay, which may be attributed to more-resistant cases of AWS. When propofol was compared with dexmedetomidine as adjuncts in AWS, both agents showed similar benzodiazepine- and haloperidol-sparing effects. Dexmedetomidine was associated with more numerical rates of bradycardia, while propofol was associated with more numerical instances of hypotension. Dexmedetomidine was used more frequently in nonintubated patients. The available data assessing the utility of propofol for AWS exhibited significant heterogeneity. Propofol may be useful in a specific population of patients with AWS, limited to those who are not clinically responding to first-line therapy with benzodiazepines. Specifically, propofol should be considered in patients who are refractory to or not candidates for other adjuvant therapies, patients already requiring mechanical ventilation, or those with seizure activity or refractory delirium tremens. In severe, refractory AWS, adjuvant therapy with propofol may be considered but requires further research to recommend its use either preferentially or as monotherapy., (© 2016 Pharmacotherapy Publications, Inc.)

Introduction: alcohol is a psychotropic depressant of the central nervous system (CNS) that promotes simultaneous changes in several neuronal pathways, exerting a profound neurological impact that leads to various behavioral and biological alterations., Objectives: to describe the effects of alcohol on the CNS, identifying the signaling pathways that are modified and the biological effects resulting from its consumption., Methods: a literature review was conducted and articles published in different languages over the last 15 years were retrieved., Results: the studies reviewed describe the direct effect of alcohol on several neurotransmitter receptors (gamma-aminobutyric acid [GABA], glutamate, endocannabinoids AEA and 2-AG, among others), the indirect effect of alcohol on the limbic and opioid systems, and the effect on calcium and potassium channels and on proteins regulated by GABA in the hippocampus., Discussion and Conclusion: the multiple actions of alcohol on the CNS result in a general effect of psychomotor depression, difficulties in information storage and logical reasoning and motor incoordination, in addition to stimulating the reward system, a fact that may explain the development of addiction. Knowledge on the neuronal signaling pathways that are altered by alcohol allows the identification of effectors which could reduce its central action, thus, offering new therapeutic perspectives for the rehabilitation of alcohol addicts.

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.

This paper evaluates the relation between Alcohol Withdrawal Syndrome tremors in the left and right hands of patients. By analyzing 122 recordings from 61 patients in emergency departments, we found a weak relationship between the left and right hand tremor frequencies (correlation coefficient of 0.63). We found a much stronger relationship between the expert physician tremor ratings (on CIWA-Ar 0-7 scale) of the two hands, with a correlation coefficient of 0.923. Next, using a smartphone to collect the tremor data and using a previously developed model for obtaining estimated tremor ratings, we also found a strong correlation (correlation coefficient of 0.852) between the estimates of each hand. Finally, we evaluated different methods of combining the data from the two hands for obtaining a single tremor rating estimate, and found that simply averaging the tremor ratings of the two hands results in the lowest tremor estimate error (an RMSE of 0.977). Looking at the frequency dependence of this error, we found that higher frequency tremors had a much lower estimation error (an RMSE of 1.102 for tremors with frequencies in the 3-6Hz range as compared to 0.625 for tremors with frequencies in the 7-10Hz range).

Aims: While the relationship between chronic exposure to alcohol and neurobiological damage is well established, deleterious brain effects of binge drinking in youths have only recently been studied., Methods: Narrative review of studies of brain disturbances associated with binge drinking as assessed by neuroimaging (EEG and IRMf techniques in particular) in adolescent drinkers., Results: Some major points still deserved to be investigated; directions for future research are suggested., Conclusions: Information and prevention programs should emphasize that binge drinking is not just inoffensive social fun, but if carried on, may contribute to the onset of cerebral disturbances possibly leading to alcohol dependence later in life.

In this paper, we propose a signal processing method of assessing the severity tremors caused by alcohol withdrawal (AW) syndrome. We have developed an iOS application to calculate the Clinical Institute Withdrawal Assessment (CIWA) score which captures iPod movements using the built-in accelerometer in order to reliably estimate the tremor severity component of the score. We report on the characteristics of AW tremor, the accuracy of electronic assessment of tremor compared to expert clinician assessment, and the potential for using signal processing assessment to differentiate factitious from real tremor in patients seen in the emergency department, as well as in nurses mimicking a tremor. Our preliminary results are based on 84 recordings from 61 subjects (49 patients, 12 nurses). In general we found a linear relationship between energy measured by the accelerometer (in the 4.4-10 Hz range) and the expert rating of tremor severity. Additionally, we demonstrate that 75% of the recordings from patients with actual AW syndrome had a mean peak frequency higher than 7 Hz whereas only 17% of the nurses' factitious tremors were above 7 Hz, suggesting that tremor above 7 Hz could be a potential discriminator of real versus factitious tremors.

Alcohol-related diseases of the nervous system are caused by excessive exposures to alcohol, with or without co-existing nutritional or vitamin deficiencies. Toxic and metabolic effects of alcohol (ethanol) vary with brain region, age/developmental stage, dose, and duration of exposures. In the mature brain, heavy chronic or binge alcohol exposures can cause severe debilitating diseases of the central and peripheral nervous systems, and skeletal muscle. Most commonly, long-standing heavy alcohol abuse leads to disproportionate loss of cerebral white matter and impairments in executive function. The cerebellum (especially the vermis), cortical-limbic circuits, skeletal muscle, and peripheral nerves are also important targets of chronic alcohol-related metabolic injury and degeneration. Although all cell types within the nervous system are vulnerable to the toxic, metabolic, and degenerative effects of alcohol, astrocytes, oligodendrocytes, and synaptic terminals are major targets, accounting for the white matter atrophy, neural inflammation and toxicity, and impairments in synaptogenesis. Besides chronic degenerative neuropathology, alcoholics are predisposed to develop severe potentially life-threatening acute or subacute symmetrical hemorrhagic injury in the diencephalon and brainstem due to thiamine deficiency, which exerts toxic/metabolic effects on glia, myelin, and the microvasculature. Alcohol also has devastating neurotoxic and teratogenic effects on the developing brain in association with fetal alcohol spectrum disorder/fetal alcohol syndrome. Alcohol impairs function of neurons and glia, disrupting a broad array of functions including neuronal survival, cell migration, and glial cell (astrocytes and oligodendrocytes) differentiation. Further progress is needed to better understand the pathophysiology of this exposure-related constellation of nervous system diseases and better correlate the underlying pathology with in vivo imaging and biochemical lesions.

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

Recent work suggests that sex differences exist with regard to both the nature of neuroadaptation to alcohol during the development of dependence, and possibly, the neurodegenerative consequences of alcohol dependence. Volumetric studies in human samples show that females may demonstrate increased volumetric brain loss with equal or lesser dependence histories than males. Furthermore, animal studies demonstrate sex differences in glutamatergic, GABAergic, and adenosinergic receptor signaling and endocrine responses following prolonged alcohol exposure. These differences may influence the development of dependence, neuronal function, and viability, particularly during alcohol withdrawal. The present review discusses the current state of knowledge in this regard. It is concluded that there exists a clear need for a more extensive examination of potential sex differences in neurodegenerative consequences of alcohol dependence in men and women, particularly with regard to the role that alterations in amino acid signaling and hypothalamic-pituitary-adrenal axis function may play. Furthermore, we note the need for expanded examination of the unique role that alcohol withdrawal-associated neuronal activity may have in the development of dependence-associated neurotoxicity.

Objective: We investigated the association between mean corpuscular volume (MCV), carbohydrate-deficient transferrin (CDT), and gamma-glutamyl transferase (GGT) levels and gray and white brain matter in male drinkers to find out which if any of these biomarkers of alcohol consumption is indicative for alcohol-related differences in brain volume., Method: Plasma levels of CDT, GGT, and MCV and magnetic resonance imaging-determined brain gray and white matter volumes were assessed in 55 male drinkers. Current alcohol intake and lifetime alcohol intake were determined by self-report measures. The relationship between MCV, CDT, and GGT and brain volumes was explored using multiple linear regression analyses., Results: There was a significant negative relationship between plasma GGT and MCV levels and gray matter volumes. Middle-aged male drinkers with highly elevated GGT and MCV levels (twice the standard deviation above the mean) have 4-12% less parietal and occipital gray matter than males with average GGT and MCV levels. There was no association between CDT levels and brain gray or white matter., Conclusions: Elevated GGT and MCV levels may be indicative of alcohol-related gray-matter decline in male drinkers. The link with GGT may reflect that elevated GGT levels are a sign of increased oxidative stress. The link with MCV levels may reflect a decreased oxygen transport to the brain., (Copyright © 2012 John Wiley & Sons, Ltd.)

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.

Background: Contextual memory, or memory for source details, is an important aspect of episodic memory and has been implicated in alcohol-induced fragmentary blackouts (FBs). Little is known, however, about how neural functioning during contextual memory processes may differ between individuals with and without a history of FB. This study examined whether neural activation during a contextual memory task differed by history of FB and acute alcohol consumption., Methods: Twenty-four matched individuals with (FB+; n = 12) and without (FB-; n = 12) a history of FBs were recruited from a longitudinal study of alcohol use and behavioral risks and completed a laboratory beverage challenge followed by 2 functional magnetic resonance imaging (fMRI) sessions under no alcohol and alcohol (breath alcohol concentration = 0.08%) conditions. Task performance and brain hemodynamic activity during a block design contextual memory task were examined across 48 fMRI sessions., Results: Groups demonstrated no differences in performance on the contextual memory task, yet exhibited different brain response patterns after alcohol intoxication. A significant FB group by beverage interaction emerged in bilateral dorsolateral prefrontal cortex and posterior parietal cortex with FB- individuals showing greater blood oxygenation level-dependent response after alcohol exposure (p < 0.05)., Conclusions: Alcohol had differential effects on neural activity for FB+ and FB- individuals during recollection of contextual information, perhaps suggesting a neurobiological mechanism associated with alcohol-induced FB., (Copyright © 2012 by the Research Society on Alcoholism.)

Background: Alcohol withdrawal syndrome is associated with an increased incidence of cardiac arrhythmias and sudden cardiac death. Heart rate turbulence (HRT) parameters were applied during withdrawal to estimate cardiac regulation during treatment with clomethiazole., Methods: Twenty-two patients suffering from alcohol withdrawal syndrome were included in the study. Heart rate regulation was obtained by means of Holter ECG analyzing time intervals before medication, and 2 and 6h after medication. Slope and onset of HRT were calculated in addition to heart rate variability (HRV) parameters. Furthermore, we calculated the slope and the onset of ectopic beat-like events., Results: Heart rate variability parameters indicated a minor reduction of vagal modulation during withdrawal syndrome. Especially, the fractal scaling exponent BBI alpha1 (4-16) indicated the autonomic shift. In contrast to HRV parameters, no significant changes were observed in the HRT parameters. Significant correlations were observed between severity of withdrawal, as assessed by the AWS scale, and the fractal scaling exponent BBI alpha2 (16-64), and the onset and the slope of HRT of ectopic beat-like activity., Conclusion: Increased sympathetic modulation during withdrawal and clomethiazole treatment is not associated with changes of heart rate turbulence parameters predictive of cardiac death after myocardial infarction., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Early-life stress has been shown to increase susceptibility to anxiety and substance abuse. Disrupted activity within the anterior insular cortex (AIC) has been shown to play a role in both of these disorders. Altered serotonergic processing is implicated in controlling the activity levels of the associated cognitive networks. We therefore investigated changes in both serotonin receptor expression and glutamatergic synaptic activity in the AIC of alcohol-drinking rhesus monkeys. We studied tissues from male rhesus monkeys raised under two conditions: Male rhesus monkeys (1) "mother reared" (MR) by adult females (n=9) or (2) "Nursery reared" (NR), that is, separated from their mothers and reared as a separate group under surrogate/peer-reared conditions (n=9). The NR condition represents a long-standing and well-validated nonhuman primate model of early life stress. All monkeys were trained to self-administer ethanol (4% w/v) or an isocaloric maltose-dextrin control solution. Subsets from each rearing condition were then given daily access to ethanol, water, or maltose-dextrin for 12 months. Tissues were collected at necropsy and were further analyzed. Using real time RT-PCR we found that ethanol-naive, NR monkeys had lower AIC levels of 5-HT(1A) and 5-HT(2A) receptor mRNA compared with ethanol-naive, MR animals. Although NR monkeys consumed more ethanol over the 12-month period compared with MR animals, both MR and NR animals expressed greater 5-HT(1A) and 5-HT(2A) receptor mRNA levels following chronic alcohol self-administration. The interaction between nursery-rearing conditions and alcohol consumption resulted in a significant enhancement of both 5-HT(1A) and 5-HT(2A) receptor mRNA levels such that lower expression levels observed in nursery-rearing conditions were not found in the alcohol self-administration group. Using voltage clamp recordings in the whole cell configuration we recorded excitatory postsynaptic currents in both ethanol-naive and chronic self-administration groups of NR and MR monkeys. Both groups that self-administered ethanol showed greater glutamatergic activity within the AIC. This AIC hyperactivity in MR alcohol-consuming monkeys was accompanied by an increased sensitivity to regulation by presynaptic 5-HT(1A) receptors that was not apparent in the ethanol-naive, MR group. Our data indicate that chronic alcohol consumption leads to greater AIC activity and may indicate a compensatory upregulation of presynaptic 5-HT(1A) receptors. Our results also indicate that AIC activity may be less effectively regulated by 5-HT in ethanol-naive NR animals than in NR monkeys in response to chronic ethanol self-administration. These data suggest possible mechanisms for increased alcohol seeking and possible addiction potential among young adults who had previously experienced early-life stress that include disruptions in both AIC activity and serotonin system dynamics., (Copyright © 2012 IBRO. All rights reserved.)

There is strong evidence that vascular risk factors play a role in the development of Alzheimer's disease (AD) or vascular dementia (vaD). Ethanol (EtOH) and cholesterol are such vascular risk factors, and we recently showed that hypercholesterolemia causes pathologies similar to AD [Ullrich et al. (2010) Mol Cell Neurosci 45, 408-417]. The aim of this study was to investigate the effects of long-term (12 months) EtOH treatment (20% v/v in drinking water) alone or long-term 5% cholesterol diet alone or a combination (mix) in adult Sprague-Dawley rats. Long-term EtOH treatment (plasma EtOH levels 58±23 mg/dl) caused significant impairment of spatial memory, reduced the number of choline acetyltransferase- and p75 neurotrophin receptor-positive nucleus basalis of Meynert neurons, decreased cortical acetylcholine, elevated cortical monocyte chemoattractant protein-1 and tissue-type plasminogen activator, enhanced microglia, and markedly induced anti-rat immunoglobulin G-positive blood-brain barrier leakage. The effect of long-term hypercholesterolemia was similar. Combined long-term treatment of rats with 20% EtOH and 5% cholesterol (mix) did not potentiate treatment with EtOH alone, but instead counteracted some of the EtOH-associated effects. In conclusion, our data show that vascular risk factors EtOH and cholesterol play a role in cognitive impairment and possibly vaD., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Chronic ethanol exposure leads to dysregulation of the hypothalamic-pituitary-adrenal axis, leading to changes in glucocorticoid release and function that have been proposed to maintain pathological alcohol consumption and increase vulnerability to relapse during abstinence. The objective of this study was to determine whether mifepristone, a glucocorticoid receptor antagonist, plays a role in ethanol self-administration and reinstatement. Male, Long-Evans rats were trained to self-administer either ethanol or sucrose in daily 30 min operant self-administration sessions using a fixed ratio 3 schedule of reinforcement. Following establishment of stable baseline responding, we examined the effects of mifepristone on maintained responding and yohimbine-induced increases in responding for ethanol and sucrose. Lever responding was extinguished in separate groups of rats and animals were tested for yohimbine-induced reinstatement and corticosterone release. We also investigated the effects of local mifepristone infusions into the central amygdala (CeA) on yohimbine-induced reinstatement of ethanol- and sucrose-seeking. In addition, we infused mifepristone into the basolateral amygdala (BLA) in ethanol-seeking animals as an anatomical control. We show that both systemic and intra-CeA (but not BLA) mifepristone administration suppressed yohimbine-induced reinstatement of ethanol-seeking, while only systemic injections attenuated sucrose-seeking. In contrast, baseline consumption, yohimbine-induced increases in responding, and circulating CORT levels were unaffected. The data indicate that the CeA plays an important role in the effects of mifepristone on yohimbine-induced reinstatement of ethanol-seeking. Mifepristone may be a valuable pharmacotherapeutic strategy for preventing relapse to alcohol use disorders and, as it is FDA approved, may be a candidate for clinical trials in the near future.

Corticotropin-releasing hormone (CRH) and its receptor, CRH receptor-1 (CRHR1), have a key role in alcoholism. Especially, post-dependent and stress-induced alcohol intake involve CRH/CRHR1 signaling within extra-hypothalamic structures, but a contribution of the hypothalamic-pituitary-adrenal (HPA) axis activity might be involved as well. Here we examined the role of CRHR1 in various drinking conditions in relation to HPA and extra-HPA sites, and studied relapse-like drinking behavior in the alcohol deprivation model (ADE). To dissect CRH/CRHR1 extra-HPA and HPA signaling on a molecular level, a conditional brain-specific Crhr1-knockout (Crhr1(NestinCre)) and a global knockout mouse line were studied for basal alcohol drinking, stress-induced alcohol consumption, deprivation-induced intake, and escalated alcohol consumption in the post-dependent state. In a second set of experiments, we tested CRHR1 antagonists in the ADE model. Stress-induced augmentation of alcohol intake was lower in Crhr1(NestinCre) mice as compared with control animals. Crhr1(NestinCre) mice were also resistant to escalation of alcohol intake in the post-dependent state. Contrarily, global Crhr1 knockouts showed enhanced stress-induced alcohol consumption and a more pronounced escalation of intake in the post-dependent state than their control littermates. Basal intake and deprivation-induced intake were unaltered in both knockout models when compared with their respective controls. In line with these findings, CRHR1 antagonists did not affect relapse-like drinking after a deprivation period in rats. We conclude that CRH/CRHR1 extra-HPA and HPA signaling may have opposing effects on stress-related alcohol consumption. CRHR1 does not have a role in basal alcohol intake or relapse-like drinking situations with a low stress load.

Chronic alcohol exposure inhibits insulin and insulin-like growth factor signaling in the liver and brain by impairing the signaling cascade at multiple levels. These alterations produced by alcohol cause severe hepatic and central nervous system insulin resistance as the cells fail to adequately transmit signals downstream through Erk/mitogen-activated protein kinase (MAPK), which is needed for DNA synthesis and liver regeneration, and phosphatidylinositol 3-kinase (PI3K), which promotes growth, survival, cell motility, glucose utilization, plasticity, and energy metabolism. The robust inhibition of insulin signaling in liver and brain is augmented by additional factors involving the activation of phosphatases such as phosphatase and tensin homologue (PTEN), which further impairs insulin signaling through PI3K/Akt. Thus, intact insulin signaling is important for neuronal survival. Chronic alcohol consumption produces steatohepatitis, which also promotes hepatic insulin resistance, oxidative stress and injury, with the attendant increased generation of "toxic lipids" such as ceramides that increase insulin resistance. The PI3K/Akt signaling cascade is altered by direct interaction with ceramides as well as through PTEN upregulation as a downstream target gene of enhanced p53 transcriptional activity. Cytotoxic ceramides transferred from the liver to the blood can enter the brain due to their lipid-soluble nature, and thereby exert neurodegenerative effects via a liver-brain axis. We postulate that the neurotoxic and neurodegenerative effects of liver-derived ceramides activate pro-inflammatory cytokines and increase lipid adducts and insulin resistance in the brain to impair cognitive and motor function. These observations are discussed in the context of insulin sensitizers as potential cytoprotective agents against liver and brain injury induced by alcohol., (© 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Frontoparietal connections underlie key executive cognitive functions. Abnormalities in the frontoparietal network have been observed in chronic alcoholics and associated with alcohol-related cognitive deficits. It remains unclear whether neurobiological differences in frontoparietal circuitry exist in substance-naïve youth who are at-risk for alcohol use disorders. This study used functional connectivity magnetic resonance imaging and diffusion tensor imaging to examine frontoparietal connectivity and underlying white matter microstructure in 20 substance-naïve youth with a family history of alcohol dependence and 20 well-matched controls without familial substance use disorders. Youth with a family history of alcohol dependence showed significantly less functional connectivity between posterior parietal and dorsolateral prefrontal seed regions (ps<.05), as compared to family history negative controls; however, they did not show differences in white matter architecture within tracts subserving frontoparietal circuitry (ps>.34). Substance-naïve youth with a family history of alcohol dependence show less frontoparietal functional connectivity in the absence of white matter microstructural abnormalities as compared to youth with no familial risk. This may suggest a potential neurobiological marker for the development of substance use disorders., (Published by Elsevier B.V.)

NMDA receptors have been hypothesized to play a role in various aspects of ethanol-related phenotypes, notably in ethanol withdrawal. However, the role of each of the specific subunits remains unclear. To address this issue, mice that are heterozygous for the NR1 deletion, and thus have a reduction in functional NMDA receptors, were examined for ethanol consumption and acute ethanol withdrawal. Additionally, mice were examined for the level of vocalization following footshock, and behavior in an elevated plus maze, to determine their responses to stress. In these behavioral tests, NR1 heterozygous mice were shown to consume significantly higher levels of ethanol in the two bottle-choice test showing a possible role for this receptor in ethanol consumption. Analysis of acute withdrawal found that the heterozygous mice exhibit lower levels of handling-induced convulsions consistent with a role in ethanol sensitivity or withdrawal. In contrast, no effects on stress-related phenotypes were detected. Levels of NR2A-NR2D subunits of the NMDA receptor in specific brain regions were compared between NR1+/- mice and wild-type controls to assess whether the behavioral responses were specific to the diminution in NR1 expression or whether these changes could be due to secondary changes in expression of other NMDA subunits. Real-time quantitative PCR, Western blot and immunohistochemistry were used to examine expression levels in the hippocampus, neocortex, striatum and cerebellum. For the majority of the subunits, no differences were found between the wild-type and heterozygous mice in any of the brain regions. However, the NR2B subunit exhibited differences in expression of RNA in the hippocampus and protein levels in multiple brain regions, between wild-type and NR1+/- mice. These results show that NR1 plays a role, through mechanisms as yet unknown, in the expression of NR2 subunits in a region and subtype specific manner. This provides evidence of the effects of altered levels of NR1 expression on ethanol withdrawal and consumption, and suggests that concomitant changes in the levels of NR2B may contribute to that effect., (Published by Elsevier Inc.)

The dentate gyrus (DG) is a region of the hippocampus intimately involved with learning and memory. Prenatal exposure to either stress or ethanol can reduce long-term potentiation (LTP) in the male hippocampus but there is little information on how these prenatal events affect LTP in the adolescent female hippocampus. Previous studies suggest that deleterious effects of PNEE can, in part, be mediated by corticosterone, suggesting that prenatal stress might further enhance any alterations to LTP induced PNEE. When animals were exposed to a combination of prenatal stress and PNEE distinct sex differences emerged. Exposure to ethanol throughout gestation significantly reduced DG LTP in adolescent males but enhanced LTP in adolescent females. Combined exposure to stress and ethanol in utero reduced the ethanol-induced enhancement of LTP in females. On the other hand, exposure to stress and ethanol in utero did not alter the ethanol-induced reduction of LTP in males. These results indicate that prenatal ethanol and prenatal stress produce sex-specific alterations in synaptic plasticity in the adolescent hippocampus., (Copyright © 2010 Wiley Periodicals, Inc., Inc.)

Ethanol exposure during development is the leading known cause of mental retardation and can result in characteristic physiological and cognitive deficits, often termed Fetal Alcohol Spectrum Disorders (FASD). Previous behavioral findings using rat models of FASD have suggested that there are changes in the nucleus accumbens (NAC) and medial prefrontal cortex (mPFC) following ethanol exposure during development. This study used a rat model of FASD to evaluate dendritic morphology in both the NAC and mPFC and cell number in the NAC. Dendritic morphology in mPFC and NAC was assessed using a modified Golgi stain and analyzed via three dimensional reconstructions with Neurolucida (MBF Bioscience). Cell counts in the NAC (shell and core) were determined using an unbiased stereology procedure (Stereo Investigator (MBF Bioscience)). Perinatal ethanol exposure did not affect neuronal or glial cell population numbers in the NAC. Ethanol exposure produced a sexually dimorphic effect on dendritic branching at one point along the NAC dendrites but was without effect on all other measures of dendritic morphology in the NAC. In contrast, spine density was reduced and distribution was significantly altered in layer II/III neurons of the mPFC following ethanol exposure. Ethanol exposure during development was also associated with an increase in soma size in the mPFC. These findings suggest that previously observed sexually dimorphic changes in activation of the NAC in a rat model of FASD may be due to altered input from the mPFC., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Endothelial dysfunction (EF) is a central phenomenon in a variety of conditions associated with increased cardiovascular morbidity. Here, we investigated EF during acute alcohol withdrawal syndrome before and 24h after medication. We aimed to analyze microcirculation, applying the post-occlusive reactive hyperemia (PORH) test and spectral analysis of skin vasomotion as markers of EF. Additionally, we explored whether segmentation of spectral analysis data may disclose more detailed information on dynamic blood flow behavior., Methods: We investigated 30 unmedicated patients during acute alcohol withdrawal syndrome and matched controls. Patients were reinvestigated after 24h when half of them had been treated with clomethiazole. Capillary blood flow was assessed on the right forearm after compression of the brachial artery. Parameters of PORH such as time to peak (TP), slope and PORH indices were calculated. Spectral analysis was performed in order to study five different frequency bands. Withdrawal symptoms were quantified by means of the alcohol withdrawal scale (AW scale)., Results: We observed a blunted hyperemic response in patients after occlusion of the brachial artery indicated by significantly increased TP and decreased PORH indices. In contrast, vasomotion as investigated by spectral analysis was not altered. Segmentation analysis revealed some alterations in the cardiac band at rest, and indicated differences between treated and untreated patients after 24h., Conclusion: Our results suggest peripheral endothelial dysfunction in patients during acute alcohol withdrawal. No major influence of treatment was observed. Future studies need to address the relation of EF to cardiac morbidity during alcohol withdrawal., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

To date, joint use of alcohol (EtOH) and methamphetamine (MA) represents a specific combination of polydrug abuse. Repeated administrations of EtOH, MA, and combined EtOH and MA were assessed for their effects on brain cell toxicity, cell mitosis and anxiety/depression-like behavior. We found that repeated co-administrations of EtOH and MA produced profound anxiogenic effects. Specifically, combined EtOH and MA decreased open arm exploratory responses in the elevated plus maze test. Moreover, combined EtOH and MA significantly decreased immobile responses in the tail suspension test. MA, EtOH, and their combination all reduced the number of NeuN-positive cells in amygdala (Amg), while neither of them altered the number of NeuN-positive cells in striatum (St) or prefrontal cortex (PFC). Combined EtOH and MA decreased the number of NeuN-positive cells in dentate gyrus (DG). EtOH, MA, and combined EtOH and MA all diminished comparable number of GFAP-positive cells in Amg, DG, and St. Neither of these treatment affected the number of GFAP-positive cells in PFC. EtOH, MA, and combined EtOH and MA generated comparable inhibiting effects on cell proliferation in the subventricular zone (SVZ) and DG. These results, taken together, suggest that repeated co-administrations of MA and EtOH may produce an observable anxiogenic effect. This combination-produced anxiogenic effect could be associated with neuronal loss in the dentate gurus. In contrast, such an anxiogenic effect is less likely related to this combination-caused glial toxicity in limbic regions or cell proliferation-inhibiting effect in the SVZ or DG.

Decreased cognitive control over prepotent responses has been hypothesized to contribute to ethanol-induced behavioral disinhibition. However, the effects of ethanol on specific cognitive domains associated with decision making have not been extensively studied. We examined the impact of acute ethanol administration on cognitive performance of nonhuman primates. Studies were conducted using 0.2, 0.5, and 1 g/kg intravenous ethanol in rhesus macaques performing touch screen-based tasks examining stimulus discrimination, stimulus reversal, and stimulus response performance. The impact on attentional processing was also evaluated. Ethanol reduced the accuracy of reversal performance marginally at 0.2 g/kg and significantly at 0.5 g/kg. This effect was selective given an absence of impairment on the stimulus discrimination and stimulus response tasks at these doses. Performance on stimulus discrimination was impaired at 1.0 g/kg, which prevented determination of reversal performance. Analysis of post-error response times demonstrated that error processing was impaired at both 0.2 and 0.5 g/kg. Ethanol also increased the number of omissions and delayed responses on an attentional task, suggesting more frequent attentional lapses. These data demonstrate that cognitive function mediated by specific prefrontal cortical brain regions is particularly sensitive to ethanol and suggest specific cognitive mechanisms that may underlie harmful decisions made at low doses of ethanol.

Adolescent alcohol exposure (AAE) may exert long-term effects on the adult brain. Here, we tested the hypothesis that the brain regions affected include the rat hypothalamic-pituitary-adrenal (HPA) axis. Specifically, we examined the consequences of AAE [postnatal days (PND) 28-42] on the HPA axis-related brain circuitry of male rats challenged with an intragastric (ig) administration of alcohol in young adulthood (PND 61-62). Adolescent rats were exposed to alcohol vapors, while controls did not receive the drug. The mean blood alcohol level in adolescence on PND 40 was 212.8±5.7 mg %. Using immunohistochemistry and in situ hybridization procedures, we measured signals for c-fos and corticotropin releasing factor (CRF) in the paraventricular nucleus (PVN) of the hypothalamus, as well as signals for c-fos and phenylethanolamine N-methyltransferase (PNMT) in the adrenergic brain stem regions (C1 and C2). PVN CRF mRNA expression was significantly blunted in AAE rats tested at PND 61-62, compared to their controls. These animals also displayed a significant increase in the mean number of PNMT-ir cells/brain stem section in the C2 area. Collectively, these results suggest that exposure to alcohol vapors during adolescence exerts long-term effects on the ability of the PVN to mount a response to an acute alcohol administration in young adulthood, possibly mediated by medullary catecholamine input to the PVN., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

The transcription regulator, neuron-restrictive silencer factor (NRSF), also known as repressor element-1 silencing transcription factor (REST), plays an important role in neurogenesis and various neuronal diseases such as ischaemia, epilepsy, and Huntington's disease. In these disease processes, neuronal loss is associated with abnormal expression and/or localization of NRSF. Previous studies have demonstrated that NRSF regulates the effect of ethanol on neuronal cells in vitro, however, the role of NRSF in ethanol-induced neuronal cell death remains unclear. We generated nrsf conditional knockout mice using the Cre-loxP system to disrupt neuronal expression of nrsf and its truncated forms. At postnatal day 6, ethanol significantly increased the expression of REST4, a neuron-specific truncated form of NRSF, in the brains of wild type mice, and this effect was diminished in nrsf conditional knockout mice. The apoptotic effect of ethanol was pronounced in multiple brain regions of nrsf conditional mutant mice. These results indicate that NRSF, specifically REST4, may protect the developing brain from ethanol, and provide new evidence that NRSF can be a therapeutic target in foetal alcohol syndrome (FAS)., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

This paper presents BrainNetVis, a tool which serves brain network modelling and visualization, by providing both quantitative and qualitative network measures of brain interconnectivity. It emphasizes the needs that led to the creation of this tool by presenting similar works in the field and by describing how our tool contributes to the existing scenery. It also describes the methods used for the calculation of the graph metrics (global network metrics and vertex metrics), which carry the brain network information. To make the methods clear and understandable, we use an exemplar dataset throughout the paper, on which the calculations and the visualizations are performed. This dataset consists of an alcoholic and a control group of subjects.

Although recently published studies seem to confirm the important role displayed by acetaldehyde (ACH), the main metabolite of ethanol, in the behavioral effects of ethanol, the origin of ACH is still a matter of debate. While some authors confer more importance to the central (brain metabolism) origin of ACH, others indicate that the hepatic origin could be more relevant. In this study we have addressed this topic using an experimental approach that combines local microinjections of ethanol into the ventral tegmental area (VTA) (which guarantees the brain origin of the ACH) to induce motor activation in rats together with systemic administration (i.p.) of several doses (0, 12.5, 25 and 50 mg/kg) of D-penicillamine (DP), a sequestering agent of ACH with contrasted efficiency to abolish the behavioral effects of the drug. Our results clearly show that DP prevented in a dose-dependent manner the motor activation induced by intra-VTA ethanol, being the 50 mg/kg dose the most efficient. DP per se did not affect the basal activity of the rats. In order to determine the specificity of the DP action, we also studied the effects of DP 50 mg/kg on the DAMGO-induced motor activation after the intra-VTA administration of this mu-opioid receptors agonist. DP did not significantly modify the motor activation induced by DAMGO thus confirming the specificity of the DP effects. Our results clearly suggest that the brain-derived ACH is necessary to manifest the activating effects resulting from ethanol administration., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Several studies have shown alterations in different components of executive functioning in users of different drugs, including cannabis, cocaine and heroin. However, it is difficult to establish a specific association between the use of each of these drugs and executive alterations, since most drug abusers are polysubstance abusers, and alcohol is a ubiquitous confounding factor. Moreover, in order to study the association between consumption of different drugs and executive functioning, the patterns of quantity and duration of drugs used must be considered, given the association between these parameters and the executive functioning alteration degree. Based on the multicomponent approach to executive functions, the aims of the present study were: (i) to analyse the differential contribution of alcohol versus cocaine, heroin and cannabis use on executive functions performance; and (ii) to analyse the contribution made by the severity of the different drugs used (quantity and duration patterns) on these functions in a sample of polysubstance abusers that requested treatment for cannabis-, cocaine- or heroin-related problems. We administered measures of fluency, working memory, analogical reasoning, interference, cognitive flexibility, decision-making and self-regulation to two groups: 60 substance-dependent individuals (SDIs) and 30 healthy control individuals (HCIs). SDIs had significantly poorer performance than HCIs across all of the executive domains assessed. Results from hierarchical regression models showed the existence of common correlates of the use of alcohol, cannabis and cocaine on verbal fluency and decision-making; common correlates of quantity of cannabis and cocaine use on verbal working memory and analogical reasoning; common correlates of duration of cocaine and heroin use on shifting; and specific effects of duration of cocaine use on inhibition measures. These findings indicate that alcohol abuse is negatively associated with fluency and decision-making deficits, whereas the different drugs motivating treatment have both generalized and specific deleterious effects on different executive components.

Prenatal ethanol exposure has various deleterious effects on neuronal development and can induce various defects in developing brain, resulting in fetal alcohol syndrome (FAS). gamma-Aminobutyric acid (GABA(B)) receptor (R) is known to play an important role during the development of the central nervous system (CNS). Our study was designed to investigate the effect of ethanol (100 mM), nicotine (50 microM) (for 30 min and 1 h), vitamin C (vitC, 0.5 mM), ethanol plus vitC, and nicotine plus vitC on expression level of GABA(B1), GABA(B2)R, and protein kinase A-alpha (PKA) in prenatal rat cortical and hippocampal neurons at gestational days (GD) 17.5. The results showed that, upon ethanol and nicotine exposure, GABA(B1) and GABA(B2)R protein expression increased significantly in the cortex and hippocampus for a short (30 min) and long term (1 h), whereas only GABA(B2)R subunit was decreased upon nicotine exposure for a long term in the cortex. Furthermore, PKA expression in cortex and hippocampus increased with ethanol exposure during short term, whereas long-term exposure results increased in cortex and decreased in hippocampus. Moreover, the cotreatment of vitC with ethanol and nicotine showed significantly decreased expression of GABA(B1), GABA(B2)R, and PKA in cortex and hippocampus for a long-term exposure. Mitochondrial membrane potential, Fluoro-jade-B, and propidium iodide staining were used to elucidate possible neurodegeneration. Our results suggest the involvement of GABA(B)R and PKA in nicotine and ethanol-mediated neurodevelopmental defects and the potential use of vitC as a effective protective agent for FAS-related deficits.

Recent evidence suggests that corticotropin-releasing factor (CRF) receptor (CRFR) signaling is involved in modulating binge-like ethanol consumption in C57BL/6J mice. In this report, a series of experiments were performed to further characterize the role of CRFR signaling in binge-like ethanol consumption. The role of central CRFR signaling was assessed with intracerebroventricular (i.c.v.) infusion of the nonselective CRFR antagonist, alpha-helical CRF(9-41) (0, 1, 5, 10 microg/1 microl). The contribution of central CRF type 2 receptor (CRF(2)R) signaling was assessed with i.c.v. infusion of the selective CRF(2)R agonist, urocortin (Ucn) 3 (0, 0.05, 0.1, or 0.5 microg/1 microl). The role of the hypothalamic-pituitary-adrenal (HPA) axis was assessed by pretreating mice with intraperitoneal (i.p.) injection of (1) the corticosterone synthesis inhibitor, metyrapone (0, 50, 100, 150 mg/kg) or (2) the glucocorticoid receptor antagonist, mifepristone (0, 25, 50 mg/kg), and (3) by using radioimmunoassay to determine whether binge-like ethanol intake influenced plasma corticosterone levels. Finally, we determined whether the ability of the CRF(1)R antagonist, CP-154,526 (CP; 0, 10, 15 mg/kg, i.p.), to blunt binge-like drinking required normal HPA axis signaling by comparing the effectiveness of CP in adrenalectomized (ADX) and normal mice. Results showed that i.c.v. infusion of a 1 microg dose of alpha-helical CRF(9-41) significantly attenuated binge-like ethanol consumption relative to vehicle treatment, and i.c.v. infusion of Ucn 3 dose-dependently blunted binge-like drinking. On the other hand, metyrapone nonselectively reduced both ethanol and sucrose consumption, mifepristone did not alter ethanol drinking, and binge-like drinking did not correlate with plasma corticosterone levels. Finally, i.p. injection of CP significantly attenuated binge-like ethanol intake in both ADX and normal mice. Together, these results suggest that binge-like ethanol intake in C57BL/6J mice is modulated by CRF(1)R and CRF(2)R signaling, such that blockade of CRF(1)R or activation of CRF(2)R effectively reduces excessive ethanol intake. Furthermore, normal HPA axis signaling is not necessary to achieve binge-like drinking behavior.

Operant self-administration procedures are used to assess the neural basis of ethanol-seeking behavior under a wide range of experimental conditions. In general, rats do not spontaneously self-administer ethanol in pharmacologically meaningful amounts. This unit provides a step-by-step guide for training rats to self-administer quantities of ethanol that produce moderate to high blood-alcohol content. Different protocols are used for rats that are genetically heterogeneous versus rats that are selectively bred for high alcohol preference. Also, these protocols have different sets of advantages and disadvantages in terms of the ability to control for caloric intake and taste of solutions in operant testing. Basic self-administration protocols can also be altered to focus on different aspects of the motivational properties of ethanol (for example, those related to dependence). This unit provides multiple protocols that lead to alcohol intake in rats, which can be pharmacologically probed relative to a variety of control conditions., ((c) 2010 by John Wiley & Sons, Inc.)

The neurosteroid allopregnanolone (ALLO) is a progesterone metabolite that is one of a family of neuroactive steroids (NAS) that are potent positive allosteric modulators of gamma-aminobutyric acid(A) (GABA(A)) receptors. These GABAergic NAS are produced peripherally (in the adrenals and gonads) and centrally in the brain. Peripherally produced NAS modulate some effects of ethanol intoxication (e.g., anxiolytic, antidepressant, and anticonvulsant effects) in rodents. We have found that NAS also may be involved in the rebound neural hyperexcitability following a high ethanol dose. Removal of the adrenals and gonads (ADX/GDX) increased withdrawal severity following 4 g/kg ethanol, as measured by handling-induced convulsions (HICs) in male and female DBA/2J mice. NAS are produced through the metabolism of progesterone (PROG), deoxycorticosterone (DOC), or testosterone, which can be blocked with the administration of finasteride (FIN), a 5alpha-reductase enzyme inhibitor. The current investigation was undertaken to clarify the step(s) in the biosynthetic NAS pathway that were sufficient to restore the acute ethanol withdrawal profile in ADX/GDX mice to that seen in intact animals. Male and female DBA/2J mice underwent ADX/GDX or SHAM surgery. After recovery, separate groups of animals were administered PROG, DOC, PROG+FIN, DOC+FIN, FIN, ALLO, ganaxalone (a synthetic ALLO derivative), corticosterone, or vehicle. Animals were then administered a 4 g/kg ethanol dose and allowed to undergo withdrawal. HICs were measured for 12 h and again at 24 h. The results indicate that replacement with PROG and DOC restored the withdrawal profile in ADX/GDX animals to SHAM levels, and that this effect was blocked with co-administration of FIN. Administration of FIN alone increased the withdrawal profile in both SHAM and ADX/GDX males. These findings indicate that the increase in acute withdrawal severity after ADX/GDX may be due to the loss of GABAergic NAS, providing insight into the contribution of endogenous GABAergic NAS to ethanol withdrawal severity., (Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

The present paper summarizes the results of a number of pharmacological studies implicating the cannabinoid CB(1) receptor in the neural circuitry regulating different alcohol-related behaviors in rodents. Specifically, cannabinoid CB(1) receptor antagonists--including the prototype, rimonabant--have been reported to suppress: (a) acquisition and maintenance of alcohol drinking behavior under the 2-bottle "alcohol vs water" choice regimen; (b) the increase in alcohol intake occurring after a period of alcohol abstinence (an experimental model of alcohol relapse); (c) alcohol's reinforcing and motivational properties measured in rats trained to perform a specific task (e.g., lever-pressing) to access alcohol; (d) reinstatement of extinguished alcohol-seeking behavior triggered in rats by a nicotine challenge or presentation of cues previously associated to alcohol availability (another model of alcohol relapse). Additional data indicate that the opioid receptor antagonists, naloxone and naltrexone, synergistically potentiate the suppressing effect of rimonabant on alcohol intake and alcohol's motivational properties in rats. Conversely, the two clinical studies conducted to date (one in alcohol-dependent individuals and one in nontreatment-seeking heavy alcohol drinkers) yielded less conclusive results. Unfortunately, the recent discontinuation--due to the occurrence of some psychiatric adverse effects--of all trials with cannabinoid CB(1) receptor antagonists apparently hinders further investigations on the potential of rimonabant in the treatment of alcohol dependence.

Alcoholism and other alcohol use disorders are major public health problems, and the success rates of non-pharmacological treatment of these disorders such as psychotherapy, cognitive-behavioral therapy, group therapy, or residential treatment programs,remain only modest at best. High rates of recidivism (relapse) in alcoholics attempting to remain abstinent are prevalent worldwide. In recent years abundant evidence has accumulated demonstrating that alcoholism is a complex and multifaceted disease of the brain caused by numerous genetic, neurobiological, developmental, environmental, and socioeconomic factors that are still not yet fully understood.There is thus a great need to improve the success rates of all forms of treatment of alcoholism not only in preventing relapse, but curbing active alcohol consumption and craving. The development of improved pharmacotherapies that could be used as adjuncts to the aforementioned non-pharmacological treatment approaches is one avenue of great interest to the scientific community and the general public. Currently there are only three medications approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of alcohol abuse and alcoholism--disulfiram, naltrexone, and acamprosate. Yet medication compliance issues and the modest efficacy of these compounds leave substantial room for improvement. This special issue is devoted to reviewing the current status of these FDA approved medications in the treatment of alcoholism. In addition, preclinical and clinical evidence suggesting that other classes of medications might also be of potential use are reviewed, including anticonvulsants, GABAB receptor agonists, cholinergic receptor partial agonists, corticotropin-releasing factor and cannabinoid CB1 receptor antagonists, nociceptin receptor ligands, and the novel antipsychotic aripiprazole.