Alcohol-associated Stimuli Research Articles

Craving induction through virtual reality cue-exposure for patients with alcohol dependence in rehabilitation treatment

New therapeutic approaches for alcohol dependence (AD) include virtual reality (VR)-based treatments offering scalable options for cue exposure (CE), a well-established strategy in cognitive behavioral therapy. This study aimed to evaluate the feasibility and tolerability of a new VR-CE paradigm. On an explorative basis, factors influencing the induction of craving were examined. This single-arm monocentric clinical study included n = 21 patients with AD in inpatient rehabilitation treatment, that completed one VR-CE session including confrontation with alcohol-associated stimuli. Measurements of subjective craving before, during and after exposure, affective states, VR side effects as cybersickness and the sense of presence in VR were conducted. Craving levels during and directly after VR-CE were significantly higher than before the intervention. Craving levels 20 min after VR-CE did not significantly differ compared to those before VR-CE. Patients described a pronounced sense of presence and only mild symptoms of cybersickness. Craving was significantly correlated with cybersickness. While positive affect decreased throughout the VR exposure, negative affect did not differ significantly in pre-post-comparisons. This study shows that craving induction through our VR-CE paradigm is feasible and well-tolerated by patients with AD in long-term rehabilitation. These results contribute to the development and future research of therapeutic VR-CE approaches.

Contextuality of cognitive control deficits in alcohol dependence — pro et contra

Cognitive impairment, including cognitive control, mediates the negative social consequences of alcohol-related behavior, but few studies have examined these processes in the Russian speaking population using modern and standardized assessment methods. Thus, the aim of the study was to examine the features of cognitive control (inhibition of automatic response) and the general level of cognitive functioning in a Russianspeaking sample of alcohol-dependent individuals (AD) using quantitative assessment methods. Materials and Methods. 111 individuals diagnosed with alcohol dependence (F10.30) and 27 healthy participants were examined by using the Brief Assessment of Cognitive Functioning in Affective Disorders Battery (BAC-A) and additional tests of cognitive control (Stroop test with incongruent stimuli, Stroop test with alcohol-associated stimuli). The statistical methods were U-Mann-Whitney test, Spearman correlation coefficient, two-stage least squares regression. Results. In the AD group the indices of cognitive functioning were significantly lower in all parameters except for the subtests of verbal memory and digit sequence (p<0,05). The model of the relationship between the parameters of general cognitive functioning and cognitive control reveals that the index of incongruence to alcohol-related stimuli was a significant predictor of sampe affiliation. Discussion. The obtained results may indicate the presence of impairments of speed of mental processes, planning , verbal fluency and response inhibition function in the group of individuals with AD. In the studied group, the automatic response inhibition function mediates the general cognitive functioning only within the relevant contextual stimuli.

The Dopamine System in Mediating Alcohol Effects in Humans.

Brain-imaging studies show that the development and maintenance of alcohol use disorder (AUD) is determined by a complex interaction of different neurotransmitter systems and multiple psychological factors. In this context, the dopaminergic reinforcement system appears to be of fundamental importance. We focus on the excitatory and depressant effects of acute versus chronic alcohol intake and its impact on dopaminergic neurotransmission. Furthermore, we describe alterations in dopaminergic neurotransmission as associated with symptoms of alcohol dependence. We specifically focus on neuroadaptations to chronic alcohol consumption and their effect on central processing of alcohol-associated and reward-related stimuli. Altered reward processing, complex conditioning processes, impaired reinforcement learning, and increased salience attribution to alcohol-associated stimuli enable alcohol cues to drive alcohol seeking and consumption. Finally, we will discuss how the neurobiological and neurochemical mechanisms of alcohol-associated alterations in reward processing and learning can interact with stress, cognition, and emotion processing.

G-CuP: the effect of a forced oral glucose intake on alcohol craving and mesolimbic cue reactivity in alcohol dependence—study protocol of a randomized, double-blind, placebo-controlled crossover study

BackgroundMultiple studies indicate that a lower plasma level of the acetylated form of the appetite-regulating hormone ghrelin and higher plasma levels of insulin lead to a reduction in subjective alcohol craving and a reduced mesolimbic cue reactivity in functional magnetic resonance imaging (fMRI) when being exposed to alcohol-associated stimuli. The ghrelin level can physiologically be reduced by the induction of stomach distension and the ingestion of glucose or lipids.MethodsA total of 108 alcohol-dependent patients aged between 18 and 65 years are examined in the randomized, double-blind, placebo-controlled crossover study. After collecting demographic and psychometric data, participants take part in an alcohol exposure session. Afterwards, the participants go through the intervention condition (oral glucose intake) and the control condition (placebo intake) in a randomized order on two examination days. Blood samples are taken repeatedly (every 10 min) during the study course on both measuring days to determine changes in acetylated and total ghrelin and insulin plasma levels. In parallel, subjective alcohol craving after the glucose or placebo intake as the primary outcome is assessed using the Alcohol Urge Questionnaire (AUQ) and a visual analog scale (VAS). To examine the mesolimbic cue reactivity as the secondary outcome, a fMRI measurement is conducted while being exposed to alcohol-related stimuli. Appropriate statistical analysis will be used for the evaluation of the outcomes.DiscussionIf successful, the results of this study could offer alcohol-dependent patients a new potential option for acute short-term reduction of alcohol craving and thus prevent relapses and prolong periods of abstinence in the long term.Trial registrationGerman Clinical Trials Register DRKS00022419 (UTN: U1111-1278-9428). Retrospectively registered on September 15, 2020.

Nicotine Enhances Goal-Tracking in Ethanol and Food Pavlovian Conditioned Approach Paradigms.

RationaleNicotine promotes alcohol intake through pharmacological and behavioral interactions. As an example of the latter, nicotine can facilitate approach toward food- and alcohol-associated stimuli (“sign-tracking”) in lever-Pavlovian conditioned approach (PavCA) paradigms. However, we recently reported that nicotine can also enhance approach toward locations of reward delivery (“goal-tracking”) triggered by ethanol-predictive stimuli when the location of ethanol delivery is non-static (i.e., a retractable sipper bottle).ObjectiveTo determine whether the non-static nature of the reward location could have biased the development of goal-tracking in our previous study (Loney et al., 2019); we assessed the effect of nicotine in a lever-PavCA paradigm wherein the location of ethanol delivery was static (i.e., a stationary liquid receptacle). Then, to determine whether nicotine’s enhancement of goal-tracking is unique to ethanol-predictive stimuli, we assessed the effect of systemic nicotine on approach triggered by food-predictive stimuli in a lever-PavCA paradigm.MethodsLong–Evans rats were used in two PavCA experiments wherein a lever predicted the receipt of ethanol (15% vol/vol; experiment 1) or food (experiment 2) into a stationary receptacle. Prior to testing, rats were administered nicotine (0.4 mg/kg subcutaneously) or saline systemically.ResultsIn both experiments, nicotine increased measures of goal-tracking, but not sign-tracking.ConclusionNicotine can facilitate approach to reward locations without facilitating approach to reward-predictive stimuli. As such, conceptualization of the mechanisms by which nicotine affects behavior must be expanded to explain an enhancement of goal-tracking by nicotine.

PPARγ activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study.

Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therapeutic potential in alcohol dependence. We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving. Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated. The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-α, or MCP-1 were unaffected by pioglitazone treatment. Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence. NCT01631630.

Alcohol Use Disorder Interventions Targeting Brain Sites for Both Conditioned Reward and Delayed Gratification.

Alcohol use disorder is a destructive compulsion characterized by chronic relapse and poor recovery outcomes. Heightened reactivity to alcohol-associated stimuli and compromised executive function are hallmarks of alcohol use disorder. Interventions targeting these two interacting domains are thought to ameliorate these altered states, but the mutual brain sites of action are yet unknown. Although interventions on alcohol cue reactivity affect reward area responses, how treatments alter brain responses when subjects exert executive effort to delay gratification is not as well-characterized. Focusing on interventions that could be developed into effective clinical treatments, we review and identify brain sites of action for these two categories of potential therapies. Using activation likelihood estimation (ALE) meta-analysis, we find that interventions on alcohol cue reactivity localize to ventral prefrontal cortex, dorsal anterior cingulate, and temporal, striatal, and thalamic regions. Interventions for increasing delayed reward preference elicit changes mostly in midline default mode network regions, including posterior cingulate, precuneus, and ventromedial prefrontal cortex-in addition to temporal and parietal regions. Anatomical co-localization of effects appears in the ventromedial prefrontal cortex, whereas effects specific to delay-of-gratification appear in the posterior cingulate and precuneus. Thus, the current available literature suggests that interventions in the domains of cue reactivity and delay discounting alter brain activity along midline default mode regions, specifically in the ventromedial prefrontal cortex for both domains, and the posterior cingulate/precuneus for delay-of-gratification. We believe that these findings could facilitate targeting and development of new interventions, and ultimately treatments of this challenging disorder.

Effects of high-dose baclofen on cue reactivity in alcohol dependence: A randomized, placebo-controlled pharmaco-fMRI study

Increased functional brain response towards alcohol-associated stimuli is a neural hallmark of alcohol dependence and a promising target for pharmacotherapy. For the first time, we assessed the effects of individually titrated high-dose baclofen on cue reactivity and functional connectivity in alcohol-dependent (AD) patients in a randomized controlled trial (RCT).We investigated 23 recently detoxified AD patients and 23 matched healthy controls (HC) with a cue reactivity functional magnetic resonance imaging task. Patients were further scanned at baseline without medication and during treatment with high-dose baclofen/placebo (30–270 mg/d). Analyses were conducted for alcohol cue-elicited brain response, alcohol cue-modulated and stimulus-independent functional connectivity with left ventral tegmental area (VTA) as seed region.At baseline, AD patients (N = 23) showed increased cue-elicited brain activation in the ventral striatum (VS) compared to HC (N = 23), which was decreased at the second scanning session compared to baseline. Patients receiving baclofen (N = 10) showed a significant stronger decrease in cue-elicited brain activation in left orbitofrontal cortex (OFC), bilateral amygdala and left VTA than patients receiving placebo (N = 13). Treatment with baclofen further led to a decrease in alcohol cue-modulated functional connectivity between left VTA and left anterior cingulate cortex (ACC) as well as left medial prefrontal cortex (MPFC). Regarding clinical outcome, significantly more patients of the baclofen group remained abstinent during the high-dose period.Baclofen specifically decreased cue-elicited brain responses in areas known to be involved in the processing of salient (appetitive and aversive) stimuli. Treatment with high-dose baclofen seems to provide a pharmacological relief of this neural “warning signal” evoked by alcohol-related cues, thereby possibly supporting patients in remaining abstinent.Trial Registration Identifier of the main trial [BACLAD study] at clinicaltrials.gov: NCT01266655.

Pairing neutral cues with alcohol intoxication: new findings in executive and attention networks.

Alcohol-associated stimuli capture attention, yet drinkers differ in the precise stimuli that become paired with intoxication. Extending our prior work to examine the influence of alcoholism risk factors, we paired abstract visual stimuli with intravenous alcohol delivered covertly and examined brain responses to these Pavlovian-conditioned stimuli in fMRI when subjects were not intoxicated. Sixty healthy drinkers performed task-irrelevant alcohol conditioning that presented geometric shapes as conditioned stimuli. Shapes were paired with a rapidly rising alcohol limb (conditioned stimulus; CS+) using intravenous alcohol infusion targeting a final peak breath alcohol concentration of 0.045g/dL or saline (CS-) infusion at matched rates. On day 2, subjects performed monetary delay discounting outside the scanner to assess delay tolerance and then underwent event-related fMRI while performing the same task with CS+, CS-, and an irrelevant symbol. CS+ elicited stronger activation than CS- in frontoparietal executive/attention and orbitofrontal reward-associated networks. Risk factors including family history, recent drinking, sex, and age of drinking onset did not relate to the [CS+ > CS-] activation. Delay-tolerant choice and [CS+ > CS-] activation in right inferior parietal cortex were positively related. Networks governing executive attention and reward showed enhanced responses to stimuli experimentally paired with intoxication, with the right parietal cortex implicated in both alcohol cue pairing and intertemporal choice. While different from our previous study results in 14 men, we believe this paradigm in a large sample of male and female drinkers offers novel insights into Pavlovian processes less affected by idiosyncratic drug associations.

Differential regulation of alcohol taking and seeking by antagonism at α4β2 and α3β4 nAChRs.

Alcoholism is a serious public health problem throughout the world. Current pharmacotherapies for the treatment of this disorder are poorly effective. Preclinical and clinical findings point to nicotinic acetylcholine receptors (nAChRs) as a promising target for the development of novel and effective medications. Assuage Pharmaceuticals, in collaboration with Torrey Pines Institute for Molecular Studies, has discovered a new class of potent and selective α4β2 nAChR antagonists. Here, it was hypothesized that α4β2 nAChR antagonism is a viable approach for treatment of alcohol use disorders. When tested in rats, one lead compound, AP-202, attenuated both operant alcohol and nicotine self-administration in a paradigm in which the two reinforcers were concurrently available. The conotoxin TP2212-59, a selective α3β4 nAChR antagonist, was only effective in reducing nicotine self-administration. AP-202 also reduced alcohol but not food responding when alcohol was presented as the only reinforcer, whereas the commercially available α4β2 nAChR antagonist dihydro-β-erythroidine failed to alter alcohol self-administration. AP-202 did not block relapse-like behavior induced by previously alcohol-associated stimuli or yohimbine stress. In a reinstatement paradigm, in which alcohol seeking was triggered by a nicotine challenge, a behavior successfully inhibited by the nonselective nAChR antagonist mecamylamine, AP-202 was not effective, while pretreatment with TP2212-59 abolished nicotine-induced reinstatement of alcohol seeking. These findings suggest differential roles for α4β2 and α3β4 nAChR on alcohol taking and seeking with selective blockade of α4β2 nAChR being more implicated in modulating alcohol taking while selective blockade of α3β4 nAChR is involved in nicotine-induced alcohol seeking.

Do alcohol-dependent patients show different neural activation during response inhibition than healthy controls in an alcohol-related fMRI go/no-go-task?

Alcohol dependence is associated with impaired response inhibition and heightened cue reactivity towards alcohol-related stimuli. Several brain areas, but mainly prefrontal structures, have been linked to response inhibition in addiction. This study aimed at combining both aspects: salience of drug-associated cues and response inhibition using a go/no-go task with alcohol-associated stimuli during functional magnetic resonance imaging (fMRI). Nineteen abstinent alcohol-dependent patients (ADP) and 21 healthy control subjects (HC) were compared on blood oxygen level-dependent (BOLD) responses during successful inhibition of no-go stimuli and successful reactions to go stimuli. ADP and HC did not significantly differ in their behavioural performance in the task. However, both groups performed worse during the inhibition of alcoholic-associated stimuli compared to neutral stimuli. On the neural level, ADP displayed enhanced BOLD activity relative to HC during successful response inhibition in several areas involved in visual processing, cognitive and impulse control, including occipital structures, anterior cingulate gyrus, medial frontal gyrus and medial orbitofrontal cortex. We interpret these findings as a possible compensation strategy for impaired cognitive processing. Furthermore, the results underline the impact of salience of alcohol-related stimuli on response inhibition, which seems to affect both ADP and HC.

Response inhibition deficits: Reliability of alcohol-related assessment tasks

Abstract. Background: While models of addictive behaviour stress the role of an impairment of response inhibition when drug-dependent individuals are confronted with drug-associated stimuli, results from different studies are conflicting. However, there is a considerable lack of studies that assess the reliability of tasks to assess deficits of response inhibition when drug-associated stimuli are presented. Methods: In the present paper we present results from four different studies in which either a stop-signal task (study 1), a go/no-go task (study 2/3) or a go/no-go shifting task (study 4) with alcohol-related stimuli was administered to alcohol-dependent patients or control participants and split-half and/or test-retest reliability of the different outcome measures calculated. Results: Our results suggest that the go/no-go task and the go/no-go shifting task are more reliable tasks to assess impairment of inhibition in response to alcohol-associated stimuli than to the stop-signal task. Especially the go/no-go shifting task achieves at least acceptable split-half as well as test-retest reliability indices for outcome measure related to the presentation of alcohol-associated stimuli. Nevertheless, for alcohol-dependent patients reliability indices are generally considerably lower than for control participants and thus care should be taken when these tasks are administered to alcohol-dependent patients. Conclusion: Future studies are warranted to enhance our understanding of true effects and random error

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects.

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

Nucleus accumbens core and shell are differentially involved in general and outcome-specific forms of Pavlovian-instrumental transfer with alcohol and sucrose rewards.

Alcohol-associated stimuli contribute to relapse risk. Therefore, understanding the behavioural and neural mechanisms underlying the ability of such stimuli to promote alcohol-seeking is important for developing effective treatments for alcohol-use disorders. The Pavlovian-instrumental transfer (PIT) paradigm can be used to study the influence of Pavlovian cues on independently-trained instrumental responses earning reward. The effects can be either general, increasing the vigour of reward-related behaviours, or specific to responses that earn a common outcome. These different forms of PIT are mediated by distinct neural circuits involving the nucleus accumbens (NAC) core and shell, respectively. Here we examined the effects of pharmacological inactivation of either the NAC core or shell on PIT generated by alcohol-predictive and sucrose-predictive stimuli in rats. We found that presentations of a stimulus predicting sucrose enhanced responding for sucrose but not alcohol, suggesting an outcome-specific effect. In contrast, presentations of an alcohol-predictive stimulus enhanced responding for both alcohol and sucrose, suggesting a generally arousing effect. Inactivation of the NAC core reduced PIT and, in particular, the effect of the alcohol stimulus. Inactivation of the NAC shell reduced the specificity of the stimulus effects but left the ability of the stimuli to non-specifically invigorate responding intact, consistent with a role in mediating the specificity of PIT. Together, these results suggest that the NAC core plays a particularly important role in mediating the influence of alcohol-predictive cues on reward-seeking behaviours.

Changes on the Modulation of the Startle Reflex in Alcohol-Dependent Patients after 12 Weeks of a Cognitive-Behavioral Intervention

Aims: Little is known about changes in the modulation of the startle reflex when patients go through an alcohol-dependence treatment in an outpatient facility. In the current study, the affective modulation of the cue-related startle reflex has been used to evaluate changes in the emotional processing of alcohol-related stimuli that occurred after a standard cognitive-behavioral intervention, and to assess the outcome of this intervention. We hypothesized a ‘normalization' of the startle inhibition for the alcohol-related cues during the period of treatment. We also assumed that higher startle inhibition at baseline elicited by alcohol cues would predict the relapse on alcohol consumption during treatment. Participants: A total of 98 alcohol-dependent subjects were included who fulfilled DSM-IV criteria for alcohol dependence. A control group of 72 subjects was selected to match demographic characteristics. Measurements: All patients received a standard cognitive-behavioral therapy once a week throughout the study period. Findings: Results show that the startle response differed significantly after 12 weeks of treatment for alcohol-related, neutral and aversive stimuli between alcohol-dependent patients and controls. Low startle responses at baseline to alcohol cues predicted relapse. Conclusions: These results may indicate that the startle reflex is referred to enduring and permanent processes of cue reactivity, and that the emotional processing of alcohol-associated cues assessed with the affect-modulated startle reflex is less altered by interventions attempting to influence explicit cognitions. Furthermore, lower values of the baseline startle reflex elicited by alcohol-associated stimuli were associated with higher probability of relapse on alcohol use.

Nucleus Accumbens and Posterior Amygdala Mediate Cue-Triggered Alcohol Seeking and Suppress Behavior During the Omission of Alcohol-Predictive Cues.

Neurobiological mechanisms that influence behavior in the presence of alcohol-associated stimuli involve processes that organize behavior during the presence of these cues, and separately, regulation of behavior in their absence. However, little is known about anatomical structures that might mediate this regulation. Here we examined nucleus accumbens shell (AcbSh) as a possible neural substrate mediating behavior modulation triggered by the presence and absence of alcohol-associated environmental cues and contexts. We also examined subregions of basal amygdala nuclei- rostral basolateral (BLA) and basal posterior (BAP)- as they provide a major source of glutamatergic input to the AcbSh. Animals were trained to associate an auditory conditioning stimulus with alcohol in a discriminative context and then subsequently tested for conditioned port-entries across contexts either previously associated or not associated with alcohol. We found that, on test to the alcohol cue alone, AcbSh inactivation prevented conditioned port-entries in contexts that either were associated with alcohol or were novel, while also increasing unconditioned port-entries during the intertrial intervals. When tested to alcohol-reinforced cues, AcbSh inactivation produced more cue-trial omissions and elevated unconditioned port-entries. Interestingly, BLA and BAP inactivation produced dissociable effects. BAP but not BLA increased unconditioned port-entries, while both manipulations prevented conditioned port-entries during the alcohol-cue. We conclude that AcbSh is necessary for modulating control over behavior otherwise guided by the presence of alcohol-predictive environmental stimuli and contexts. Moreover, this role may involve integration of functionally segregated inputs from rostral and posterior portions of basal amygdala nuclei.

Is Binge Drinking in Young Adults Associated with an Alcohol-Specific Impairment of Response Inhibition?

Background/Aims: Little is known about the association of binge drinking with impulsivity related to trait- or state-like aspects of behavior. The aim of the present study was therefore to investigate whether binge drinkers show an impairment of inhibitory control in comparison to non-binge drinkers when confronted with alcohol-associated or control stimuli, and whether this is reflected in self-reported impulsivity. Methods: A go/no-go task with pictures of alcoholic and nonalcoholic beverages as well as control stimuli was administered to binge drinkers and a gender-matched group of non-binge drinkers. All participants also completed the Barratt Impulsiveness Scale (BIS-11). Results: We found an alcohol-specific impairment of response inhibition for binge drinkers only, while the groups did not differ with regard to overall response inhibition to the experimental stimuli or self-reported impulsiveness (BIS-11). In addition, the number of commission errors in response to alcohol-associated stimuli was the only significant predictor of binge drinking. Conclusion: The findings of the present study suggest that when young adults have established binge drinking as a common drinking pattern, impairment of inhibition in response to alcoholic stimuli is the only significant predictor of binge drinking, but not general impulsive behavior. i 2014 S. Karger AG, Basel

A Sustained Depressive State Promotes a Guanfacine Reversible Susceptibility to Alcohol Seeking in Rats

High rates of comorbidity between alcohol use disorder (AUD) and major depressive disorder (MDD) are reported. Preclinical models examining effects of primary depression on secondary AUD are currently absent, preventing adequate testing of drug treatment. Here, we combined social defeat-induced persistent stress (SDPS) and operant alcohol self-administration (SA) paradigms to assess causality between these two neuropsychiatric disorders. We then exploited guanfacine, an FDA-approved adrenergic agent reported to reduce drug craving in humans, against SDPS-induced modulation of operant alcohol SA. Wistar rats were socially defeated and isolated for a period of ≥9 weeks, during which depression-like symptomatology (cognitive and social behavioral symptoms) was assessed. Subsequently, animals were subjected to a 5-month operant alcohol SA paradigm, examining acquisition, motivation, extinction, and cue-induced reinstatement of alcohol seeking. The effects of guanfacine on motivation and relapse were measured at >6 months following defeat. SDPS rats exhibited significant disruption of social and cognitive behavior, including short-term spatial and long-term social memory, several months following defeat. Notably, SDPS increased motivation to obtain alcohol, and cue-induced relapse vulnerability. Guanfacine reversed the SDPS-induced effects on motivation and relapse. Together, our model mimics core symptomatology of a sustained depressive-like state and a subsequent vulnerability to alcohol abuse. We show that SDPS is strongly associated with an enhanced motivation for alcohol intake and relapse. Finally, we show that the clinically employed drug guanfacine has potential as a novel treatment option in comorbid patients, as it effectively reduced the enhanced sensitivity to alcohol and alcohol-associated stimuli.

The efficacy and biobehavioural basis of baclofen in the treatment of alcoholic liver disease (BacALD): Study protocol for a randomised controlled trial

BackgroundEffective treatments for alcohol use disorders in those with significant liver disease are critically lacking. The primary aim of the current study is to explore the effectiveness and biobehavioural basis of low and high dose baclofen in improving treatment outcomes for alcohol dependence in people with alcoholic liver disease (The BacALD study). MethodsThis double-blind, placebo-controlled study will randomize 180 participants to a 12-week regime of either baclofen (30mg/day baclofen, 75mg/day baclofen) or placebo. Participants must meet the ICD-10 criteria for alcohol dependence in addition to alcoholic liver disease (ALD) defined as the presence of symptoms and/or signs referable to liver disease or its complications with or without cirrhosis. Primary outcome measures will include total abstinence duration, and time to lapse and relapse. Furthermore, 60 of the ALD patients enrolled in the trial will also participate in a pharmacokinetic and cue-reactivity component, along with an additional 30 healthy volunteers matched for age and gender randomised to a 1week regime of either 30mg/day baclofen or 75mg/day baclofen. At week 1, plasma levels of baclofen and β-p-chlorophenol-γ-hydroxybutric acid will be measured at 0, 1 and 4h following baclofen administration and psychophysiological responses to alcohol-associated stimuli will be assessed in a cue reactivity paradigm. Recruitment commenced in late March 2013. ConclusionsThis trial will demonstrate the efficacy and safety of two doses of baclofen in patients with alcoholic liver disease and will explore the biobehavioural mechanisms of the treatment effect.

Alcohol-related cues reduce cognitive control in social drinkers

Alcohol-related stimuli attract social drinkers' attention (attentional bias). We devised a dual task to test whether attentional biases to alcohol-related stimuli are modulated by cognitive control mechanisms. Sixteen nondependent healthy social drinkers were required to respond to the direction of a central arrow (target) and to ignore adjacent congruent (low cognitive load) or incongruent (high cognitive load) distracting arrows (flankers) in the presence of alcohol-related, neutral or plain grey backgrounds. Percentages of correct responses to the target and reaction time of correct responses (latency) were recorded. The difference score of the flanker effect (latency incongruent-latency congruent) between trials when backgrounds were alcohol-related relative to when they were neutral was also computed. Latencies increased in the presence of the alcohol-related images relative to both the neutral and the grey displays, but only under high cognitive load. Response accuracy did not show this significant difference. The flanker effect difference score correlated positively with the participants' average weekly alcohol intake. The data suggest that the presence of alcohol-associated stimuli attenuates cognitive control processes in social drinkers, an effect that was associated with the participants' average weekly alcohol intake.