Abstinent Alcohol-dependent Subjects Research Articles

Reward Processing in Alcohol-Dependent Patients and First-Degree Relatives: Functional Brain Activity During Anticipation of Monetary Gains and Losses

BackgroundAccording to the reward deficiency syndrome and allostatic hypotheses, hyposensitivity of mesocorticolimbic regions to non–alcohol-related stimuli predisposes to dependence or is long-lastingly enhanced by chronic substance use. To date, no study has directly compared mesocorticolimbic brain activity during non–drug reward anticipation between alcohol-dependent, at risk, and healthy subjects. MethodsSeventy-five abstinent alcohol-dependent human subjects (mean abstinence duration 957.66 days), 62 healthy first-degree relatives of alcohol-dependent individuals, and 76 healthy control subjects without family history of alcohol dependence performed a monetary incentive delay task. Functional magnetic resonance imaging data of the anticipation phase were analyzed, during which visual cues predicted that fast response to a target would result in monetary gain, avoidance of monetary loss, or a neutral outcome. ResultsDuring gain anticipation, there were no significant group differences. During loss anticipation, abstinent alcohol-dependent subjects showed lower activity in the left anterior insula compared with healthy control subjects without family history of alcohol dependence only (Montreal Neurological Institute [MNI] −25 19 –5; t206 = 4.17, familywise error corrected p = .009). However, this effect was no longer significant when age was included as a covariate. There were no group differences between abstinent alcohol-dependent subjects and healthy first-degree relatives or between healthy first-degree relatives and healthy control subjects during loss anticipation, respectively. ConclusionsNeither the neural reward deficiency syndrome nor the allostatic hypotheses are supported by the results. Future studies should investigate whether the incentive salience hypothesis allows for more accurate predictions regarding mesocorticolimbic brain activity of subjects with alcohol dependence and healthy individuals during reward and loss anticipation and further examine the neural substrates underlying a predisposition to dependence.

Associations of NLRP3 and CARD8 gene polymorphisms with alcohol dependence and commonly related psychiatric disorders: a preliminary study.

We investigated two functional polymorphisms in NLRP3 inflammasome genes (NLRP3 rs35829419 and CARD8 rs2043211) and their association with alcohol dependence and related anxiety, depression, obsession-compulsion, or aggression in 88 hospitalised alcohol-dependent patients, 99 abstinent alcohol-dependent participants, and 94 controls, all male Caucasian. Alcohol dependence-related psychiatric disorders were assessed with the Zung Depression and Anxiety scale, Buss-Durkee Hostility Inventory, Alcohol Use Disorders Identification Test, Brief Social Phobia Scale, Obsessive Compulsive Drinking Scale, and Yale-Brown Obsessive-Compulsive Scale. For genotyping we used the allele-specific quantitative polymerase chain reaction-based methods. The three groups differed significantly in CARD8 rs2043211 distribution (P=0.049; chi-squared=9.557; df=4). The NLPR3 rs35829419 polymorphism was not significantly associated with alcohol dependence. In hospitalised alcohol-dependent patients the investigated polymorphisms were not associated with scores indicating alcohol consumption or comorbid symptoms. In abstinent alcohol-dependent subjects homozygotes for the polymorphic CARD8 allele presented with the highest scores on the Zung Anxiety Scale (p=0.048; df=2; F=3.140). Among controls, CARD8 genotype was associated with high scores on the Obsessive Compulsive Drinking Scale (P=0.027; df=2; F=3.744). In conclusion, our results reveal that CARD8 rs2043211 may play some role in susceptibility to alcohol dependence, expression of anxiety symptoms in abstinent alcohol-dependent subjects, and in obsessive compulsive drinking in healthy controls. However, further studies with larger cohorts are required to confirm these preliminary findings.

Repetitive transcranial magnetic stimulation (rTMS) in alcohol dependence: study protocol of a randomized controlled clinical trial of efficacy and working mechanisms

BackgroundHigh frequency repetitive transcranial magnetic stimulation (HF-rTMS) has gained interest as a neuromodulation treatment technique for alcohol dependence. Single sessions of HF-rTMS have consistently shown to decrease craving for substances. However, the results of randomized controlled clinical trials investigating the effect of multiple HF-rTMS sessions in alcohol dependence on abstinence rates and craving are inconsistent. Furthermore, they lack information on the effect of HF-rTMS on cognition and brain functioning.MethodsA single center, single blind, randomized controlled trial with 80 abstinent alcohol dependent subjects in treatment randomized (1:1) to either treatment as usual (TAU) plus ten sessions of active HF-rTMS or TAU plus 10 sessions of placebo/ sham HF-rTMS will be performed. The effects of ten HF-rTMS sessions on craving and neurocognitive functions are obtained. In addition a subset of participants will undergo an MR scanning session before the first and after the last HF-rTMS session in order to investigate the effect of ten HF-rTMS sessions on brain functioning. The primary outcome is the continued abstinence rate after the add-on HF-rTMS treatment.DiscussionThis study uses a randomized controlled trial to examine the clinical, neurocognitive and brain functioning effects of ten add-on HF-rTMS sessions in alcohol dependent individuals in treatment. If the add-on treatment is effective, this may add to the evidence needed for approval of this additional treatment method for alcohol dependence by regulatory authorities.Trial registrationThe Netherlands National Trial Register (NTR), NTR5291, 6-July-2015.

Lower Limbic Metabotropic Glutamate Receptor 5 Availability in Alcohol Dependence.

Animal studies suggest an important role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the pathophysiology of alcohol dependence, but direct human evidence is lacking. The goal of this study was to investigate cerebral mGlu5 availability in alcohol-dependent subjects versus controls using 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (18F-FPEB) PET. Methods: Dynamic 90-min 18F-FPEB scans combined with arterial blood sampling were acquired for 16 recently abstinent alcohol-dependent subjects and 32 age-matched controls. Regional mGlu5 availability was quantified by the 18F-FPEB total distribution volume using both a voxel-by-voxel and a volume-of-interest analysis with partial-volume effect correction. Alcohol consumption within the last 3 mo was assessed by questionnaires and by hair ethyl glucuronide analysis. Craving was assessed using the Desire for Alcohol Questionnaire. Results: mGlu5 availability was lower in mainly limbic regions of alcohol-dependent subjects than in controls (P < 0.05, familywise error-corrected), ranging from 14% in the posterior cingulate cortex to 36% in the caudate nucleus. Lower mGlu5 availability was associated with higher hair ethyl glucuronide levels for most regions and was related to a lower level of craving specifically in the middle frontal gyrus, cingulate cortex, and inferolateral temporal lobe. Conclusion: These findings provide human in vivo evidence that limbic mGlu5 has a role in the pathophysiology of alcohol dependence, possibly involved in a compensatory mechanism helping to reduce craving during abstinence.

Plasma concentrations of oleoylethanolamide and other acylethanolamides are altered in alcohol-dependent patients: effect of length of abstinence.

Acylethanolamides are a family of endogenous lipid mediators that are involved in physiological and behavioral processes associated with addiction. Recently, oleoylethanolamide (OEA) has been reported to reduce alcohol intake and relapse in rodents but the contribution of OEA and other acylethanolamides in alcohol addiction in humans is unknown. The present study is aimed to characterize the plasma acylethanolamides in alcohol dependence. Seventy-nine abstinent alcohol-dependent subjects (27 women) recruited from outpatient treatment programs and age-/sex-/body mass-matched healthy volunteers (28 women) were clinically assessed with the diagnostic interview PRISM according to the DSM-IV-TR after blood extraction for quantification of acylethanolamide concentrations in the plasma. Our results indicate that all acylethanolamides were significantly increased in alcohol-dependent patients compared with control subjects (p < 0.001). A logistic model based on these acylethanolamides was developed to distinguish alcohol-dependent patients from controls and included OEA, arachidonoylethanolamide (AEA) and docosatetraenoylethanolamide (DEA), providing a high discriminatory power according to area under the curve [AUC = 0.92 (95%CI: 0.87-0.96), p < 0.001]. Additionally, we found a significant effect of the duration of alcohol abstinence on the concentrations of OEA, AEA and DEA using a regression model (p < 0.05, p < 0.01 and p < 0.001, respectively), which was confirmed by a negative correlation (rho = -0.31, -0.40 and -0.44, respectively). However, acylethanolamides were not influenced by the addiction alcohol severity, duration of problematic alcohol use or diagnosis of psychiatric comorbidity. Our results support the preclinical studies and suggest that OEA, AEA and DEA are altered in alcohol-dependence during abstinence and that might act as potential markers for predicting length of alcohol abstinence.

Genetic variability in tryptophan hydroxylase 2 gene in alcohol dependence and alcohol-related psychopathological symptoms

Heritability plays an important role in the development and expression of alcohol dependence. The present genetic association study explored the role of TPH2 polymorphisms and their haplotypes to investigate its role in alcohol dependence and comorbid psychopathological symptoms. The sample included 101 subjects currently diagnosed as alcohol abusers, 100 abstinent alcohol-dependent subjects and 97 healthy controls. Subjects were genotyped for TPH2 rs4570625, rs1843809, rs7305115, rs4290270. TPH2 genotypes were not associated with alcohol dependence, but GGAA haplotype was less common (p=0.038) and GTAA and GGGT were more common (p=0.011 and p=0.021, respectively), in currently dependent patients compared to controls. Exploratory analysis of genotypes in currently dependent patients showed that rs1843809 was associated with depressive and aggressive traits (p=0.045 and p=0.001, respectively), rs4290270 with depressive and anxiety traits (p=0.040 and p=0.025, respectively) and rs4570625 with aggressive traits (p=0.011). In abstinent subjects rs1843809 genotype was associated with traits of social anxiety (p=0.003). Only association between rs1843809 and the BDHI score (p=0.001) and associations between GTAA haplotype and Zung Anxiety Scale and BDHI score (p=0.001 and p<0.001, respectively), in currently dependent patients remained significant after applying the Bonferroni’s correction.Our findings support a potential role of TPH2 in alcohol dependence. TPH2 genetic variability may be also associated with anxiety and aggression traits in alcohol dependent subjects.

Impulsivity in disorders of food and drug misuse.

Evidence suggests some overlap between the pathological use of food and drugs, yet how impulsivity compares across these different clinical disorders remains unclear. Substance use disorders are commonly characterized by elevated impulsivity, and impulsivity subtypes may show commonalities and differences in various conditions. We hypothesized that obese subjects with binge-eating disorder (BED) and abstinent alcohol-dependent cohorts would have relatively more impulsive profiles compared to obese subjects without BED. We also predicted decision impulsivity impairment in obesity with and without BED. Thirty obese subjects with BED, 30 without BED and 30 abstinent alcohol-dependent subjects and age- and gender-matched controls were tested on delay discounting (preference for a smaller immediate reward over a larger delayed reward), reflection impulsivity (rapid decision making prior to evidence accumulation) and motor response inhibition (action cancellation of a prepotent response). All three groups had greater delay discounting relative to healthy volunteers. Both obese subjects without BED and alcohol-dependent subjects had impaired motor response inhibition. Only obese subjects without BED had impaired integration of available information to optimize outcomes over later trials with a cost condition. Delay discounting appears to be a common core impairment across disorders of food and drug intake. Unexpectedly, obese subjects without BED showed greater impulsivity than obese subjects with BED. We highlight the dissociability and heterogeneity of impulsivity subtypes and add to the understanding of neurocognitive profiles across disorders involving food and drugs. Our results have therapeutic implications suggesting that disorder-specific patterns of impulsivity could be targeted.

Influence of OPRM1 Asn40Asp variant (A118G) on [11C]carfentanil binding potential: preliminary findings in human subjects

The Asn40Asp variant (A118G) of the μ opioid receptor (OPRM1) gene is thought to contribute to the development and treatment of alcohol dependence. Employing positron emission tomography (PET), we first examined whether the single nucleotide polymorphism (SNP) modifies binding potential (BP(ND)) of the μ-selective ligand [(11)C]carfentanil in healthy control (Con) and 5-d abstinent alcohol-dependent (AD) subjects (unblocked basal scan). Second, we examined whether the allelic variants were associated with differences in OPRM1 occupancy by naltrexone (50 mg) in AD subjects. Con and AD carriers of the G allele (AG) had lower global BP(ND) at the basal scan than subjects homozygous for the A allele (AA). In AD subjects, naltrexone occupancy was slightly higher in AG subjects (98.9%) compared to AA subjects (93.1%), but this was not significant. We are the first to demonstrate using PET in healthy normal and AD subjects that the A118G SNP alters OPRM1 availability.

1896 – Executive functions and impulsivity in alcohol dependence: focus on drinking behaviour

There is increasing consensus on the notion of addiction as a brain disorder characterized by longstanding changes in cognitive functioning, especially in so-called executive functions. Recent evidences indicate that specific components of executive functions, considered the domain of the frontal lobes, including dysfunctional impulsivity, could be considered a hallmark of addiction. Aim of the present study was to explore the domain of executive functions in abstinent non comorbid alcohol dependent subjects, in comparison with matched non clinical controls. Any relationship with impulsivity and drinking behaviour (binge drinking) was also investigated. We used a selective battery of neuropsychological tests designed to assess several components of executive functions, including fluency, working memory, analogical reasoning, interference and cognitive flexibility, attention, concentration, problem solving strategy and abstract reasoning. BIS-11 was also administered to explore impulsivity levels. Significant differences in many of the domains explored between alcohol dependent patients and controls have been founded. Intriguingly, impulsivity in alcoholics seems to not inhibit cognitive performance. Data about binge drinking will be also presented. Our results show that alcohol dependent patients present a weaker performance in all the domains referable to executive functions when compared to controls. Disruptions in inhibitory control are central to many theories of addiction; the inhibitory activities of the Frontal and Prefrontal Cortex, are particularly important when an individual needs to over-ride a reflexive response, such as a craving response to drug-related cues.

1484 – Could emotional awareness influence drinking outcomes in an alcohol dependent population?

Introduction Alexithymia has been studied in several addictive disorders with a special interest in alcohol dependence (Thorberg et al., 2009; Taieb et al., 2002). Nevertheless, recent studies failed to demonstrate the relationship with drinking outcomes (de Haan et al., 2012; Stasiewicz et al., 2012). Evaluation of emotional awareness in these populations could be added to specify the deficits of emotions’ differentiation and to understand the mechanisms underlying the maintenance of abstinence (Bochand & Nandrino, 2010; Carton et al., 2010). Aims We intend to evaluate short and long-term abstinent alcohol dependent subjects in a dimensional approach for alexithymia and emotional awareness, expecting relationship with drinking outcomes. Methods Thirty-two abstinent alcohol dependent participants and 28 matched controls were included. The two groups were assessed for anxiety (STAI state and trait) and depression (BDI-II). Alexithymia (TAS 20) and emotional awareness (Emotional Self-Awareness Questionnaire; ESQ) were also evaluated. The severity of alcohol dependence was specified with Alcohol Dependence Severity scale. Results Alexithymia was significantly higher in the group of alcohol dependent participants (50.1 vs 45.1; p=0.049). Within the alcohol dependent group, ESQ was negatively correlated to the severity of alcohol dependence (r=-0.29; p=0.028) with subscales “social awareness” and “social skills” negatively correlated to the duration of abstinence (r=-0.37; p=0.03 and r=- 0.38; p=0.01, respectively). Conclusions Alexithymia is significantly higher in the alcohol dependent group, compared to the control group, but within this group, evaluation of emotional awareness may become more interesting to evaluate the characteristics of alcohol dependent subjects and predict their drinking outcomes

Cognitive functions in abstinent alcohol-dependent patients

The objective of this cross-sectional study was to compare cognitive functioning of abstaining alcohol-dependent (AD) male patients and healthy controls as well as to investigate whether their cognitive performance varied by abstinence length. Forty-two maintaining abstinent (AD) patients and 34 healthy controls were examined. Tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) were used to assess cognitive functions. Differences in cognitive performance were found between AD patients and healthy controls. Nonverbal tasks in cognitive domains such as attention, visual memory and working memory were impaired in AD patients who presented deficits in visual episodic memory, had slower reaction time and reduced working memory span. Patients who were abstinent for less than one year made more errors in both attentional set shifting and working memory tests than healthy controls and patients with longer durations of abstinence. Impairments identified in multiple cognitive domains in abstinent alcohol-dependent subjects suggest functional deficits in extensive brain networks connecting interrelated brain structures. Attentional control and spatial working memory were less impaired in those AD patients who maintained abstinence for at least one year.

Decision Making, Impulsivity, and Personality Traits in Alcohol‐Dependent Subjects

The aim of the study was to assess the relationship among decision-making (DM) ability (as measured by the Iowa Gambling Task [IGT]), impulsivity, and temperament and character traits in a long-term abstinent alcohol-dependent sample. Twenty-six abstinent alcohol-dependent subjects, referred to a Drug Addiction Unit of the National Health Service of L'Aquila, were evaluated using the IGT, the Barratt Impulsiveness Scale, version 11 (BIS-11), and the Temperament and Character Inventory 125-item (TCI-125) version. Twenty-four control subjects were recruited and assessed with IGT only. The clinical and control samples were significantly different in their IGT performance, the former sample making disadvantageous choices leading to lower scores. Significant negative correlations between IGT total score and BIS Non-Planning Impulsivity and a trend toward significance with TCI Novelty Seeking dimension were reported. Our data confirm the results of other studies suggesting DM impairment related to impulsive dimension as an important feature in subjects with alcohol dependence: the finding suggests a role of DM impairment in increasing proneness to a chronic relapsing course.

P-95 - Executive functions, anger and impulsivity in alcohol dependence

There is increasing consensus on the notion of addiction as a brain disorder characterized by longstanding changes in cognitive functioning, especially in so-called executive functions. Recent evidences indicate that specific components of executive functions, considered the domain of the frontal lobes, including dysfunctional impulsivity, could be considered a hallmark of addiction. Aim of the present study was to explore the domain of executive functions in abstinent non comorbid alcohol dependent subjects in comparison with matched non clinical controls. Any relationship with impulsivity and anger was also investigated. Thirty Alcohol Dependent outpatients with diagnosis of Alcohol Dependence (DSM-IV-TR) and thirty matched control subjects participated to the study. We used a selective battery of neuropsychological tests designed to assess several components of executive functions, including fluency, working memory, analogical reasoning, interference and cognitive flexibility, attention, concentration, problem solving strategy and abstract reasoning (FAS for verbal fluency; Semantic Fluency; Digit span; Spatial span; Similarities; Stroop test; Wisconsin Card Sorting Test; TMT Making Test Parts A & B; Digit Symbol). BIS-11 and STAXI I and II were also administered to explore impulsivity and anger levels. Significant differences in many of the domains explored between alcohol dependent patients and controls have been founded. Furthermore, a correlation between the performance at neuropsychological tests and the score at the instruments designed to assess impulsivity and anger have been deducted. Alcohol dependence is associated with a significant impairment on executive domain. Impulsivity and anger levels, both dimensions linked with the executive capacity, seem to be altered as well.

Serum NPY and BNDF response to a behavioral stressor in alcohol-dependent and healthy control participants.

Neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF) have been implicated in both the stress response and alcohol addiction. However, few studies have assessed the NPY and BDNF response to stress in alcohol-dependent participants and the concurrent measure of NPY and BDNF has not been reported in human participants. The purpose of this study was to concurrently assess serum NPY and BDNF, as well as adrenocorticotropin (ACTH) and cortisol, in control and race- and aged-matched abstinent alcohol-dependent participants in response to a stress-inducing public-speaking task. Basal and post-stress serum values of NPY and BDNF, as well as ACTH and cortisol, were assessed in 14 abstinent alcohol-dependent and ten healthy control male participants. Basal measures were stable over short periods of time and stress induced a significant increase in both NPY (p = 0.002) and BDNF (p = 0.006) as well as ACTH (p < 0.001) and cortisol (p < 0.007). Alcohol-dependent and control groups did not significantly differ on any basal or stress-induced measure. Basal and delta responses of NPY and BDNF were not significantly correlated, and delta peak responses of NPY and BDNF did not correlate with one another or with their respective ACTH and cortisol responses. These findings reveal that both serum NPY and BDNF are responsive to behavioral stressors, although their regulatory mechanisms appear to differ from one another and those of the hypothalamic-pituitary-adrenal axis. Differences in basal and stress-induced responses of NPY and BDNF were not supported between control and abstinent alcohol-dependent subjects.

A pilot study of the effectiveness of d-cycloserine during cue-exposure therapy in abstinent alcohol-dependent subjects

Cue-exposure therapy (CET) has been advocated as a potentially effective treatment of addictive behaviours. Strategies that enhance learning may improve the outcome of CET. D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist, has been shown to facilitate extinction of learned fear in rats and augment exposure-based treatment in some anxiety disorders in man. This double-blind placebo-controlled pilot study used a cue-exposure paradigm, salient for an individual's alcohol drinking, to see if DCS would reduce cue-reactivity compared with placebo. Sixteen abstinent, alcohol-dependent individuals were randomised to receive either a single-dose (250 mg) DCS or placebo before CET sessions, separated by at least 1 week. Subjective responses were assessed using the Alcohol Urge Questionnaire (AUQ) and visual analogue scales. Cardiovascular responses were assessed using Finapres©. The cue-exposure paradigm significantly increased craving assessed with the AUQ during the first session. In subsequent sessions, the degree of craving was reduced. However, no significant difference was seen between the DCS and placebo groups in any outcome measure. The variability of responses between individuals was great with more than half the groups reporting no or very small changes in AUQ scores. This is the first human study to our knowledge to assess the efficacy of DCS in facilitating CET in alcohol dependence. The high proportion of subjects with little or no response to cue-exposure would make any effect of DCS very difficult to detect. It is important that future studies carefully consider the criteria for inclusion.

Neuropsychological assessment of impulsive behavior in abstinent alcohol-dependent subjects

Poor impulse control is thought to be one of the characteristics of alcohol addiction. The capacity to remain abstinent may be linked to cognitive bias related to three dimensions of impulsivity: motor, non-planning, and attentional impulsivity. The aim of this study was to evaluate the neuropsychological profile related to these impulsivity dimensions in alcohol-dependent patients within 15 -120 days of abstinence. We compared 31 alcohol-dependent patients to 30 matched healthy controls regarding their performances on the Continuous Performance Task, the Iowa Gambling Test, and the Wisconsin Card Sorting Test, each of which is thought to tax primarily one of the three dimensions of impulsivity just outlined. When compared to controls, alcohol-dependent patients presented more commission errors on the Continuous Performance Task; made more disadvantageous choices on the Iowa Gambling Test; and made more perseverative errors on the Wisconsin Card Sorting Test. There was no significant correlation between performance on these tests and the length of abstinence. These results suggest that deficits related to motor, non-planning and attentional components of impulsivity exist in alcohol-dependent patients, in the period immediately after acute alcohol withdrawal. These results may help guide interventions designed to prevent the risk of relapse in alcohol-abstinent patients.

P01-75 Cognitive functions, impulsivity and personality traits in alcohol dependent subjects

The term ‘decision making’ indicates the aspects of executive functions related to the ability to modulate the reward and punishment perception, in order to operate advantageous choices.Subjects with alcoholism exhibit poor decision making and high level of impulsivity.This study assesses the relationship between decision making ability, as measured by Iowa Gambling Task (IGT), and impulsivity and others temperamental and character traits in a long-term abstinent alcohol dependent sample.30 abstinent alcohol dependent subjects, referred to Drug Addiction Unit of National Health Service of L'Aquila were assessed using IGT, the Barratt Impulsiveness Scale 11-item version (BIS-11) and the Temperament and Character Inventory - 125 items (TCI-125). The mean age was 44.53 (8.66 SD) years and educational level was 9.03 years (2.52).15 control subjects were recruited from general population and assessed with IGT only (age 41.38±11.10; educational level 12.23±3.44).The clinical and the control samples significantly differ in their performance on the IGT, the former making disadvantageous choices in the task leading to lower scores. We found only a significant correlation between IGT total score and the BIS factor Non-Planning Impulsivity.The alcoholic subjects, although in a abstinent status, show difficulties to learn the task strategies and/or earn from experience to orient toward an advantageous choice pattern, supporting the hypothesis of a decision making impairment.The lack of correlation with impulsivity factors and personality traits supports the results of other studies concluding that, at dimensional level, decision making abilities may be a distinct construct.

Differences in δ- and μ-Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

Blockade of brain mu-opioid receptor (mu-OR) and delta-opioid receptor (delta-OR) was investigated in recently abstinent alcohol-dependent subjects (N=21) maintained on naltrexone. Subjects completed a 19-day inpatient protocol, which included alcohol abstinence followed by naltrexone treatment (50 mg) on days 15-19. Blood samples were collected after the first administration of naltrexone to evaluate serum levels of naltrexone and 6-beta-naltrexol. Regional brain mu-OR binding potential (BP) and delta-OR Ki was measured using [11C]carfentanil (CAR) positron emission tomography (PET) and [11C]methyl naltrindole ([11C]MeNTI) PET, respectively, before (day 5) and during naltrexone treatment (day 18). Naltrexone inhibition of [11C]CAR BP was near maximal across all brain regions of interest with little variability across subjects (mean+SD% inhibition=94.9+4.9%). Naltrexone only partially inhibited the [11C]MeNTI Ki and there was more variability across subjects (mean+SD% inhibition=21.1+14.49%). Peak serum levels of naltrexone were positively correlated with % inhibition of delta-OR Ki in neocortex and basal ganglia. Peak serum levels of naltrexone were not correlated with % inhibition of mu-OR BP. Peak levels of 6-beta-naltrexol were not significantly correlated with % inhibition of mu-OR BP or delta-OR Ki. Thus, the FDA recommended therapeutic dose of naltrexone was sufficient to produce near complete inhibition of the mu-OR in recently abstinent alcohol dependent subjects. The lower percent inhibition of delta-OR and greater variability in delta-OR blockade by naltrexone across subjects may contribute to individual differences in treatment outcomes to naltrexone. Further investigations on the relationship between individual differences in delta-OR blockade by naltrexone and clinical outcomes should be explored.

CLINICAL AND IMAGING STUDY: Imaging alcohol cue exposure in alcohol dependence using a PET 15O‐H2O paradigm: results from a pilot study

Craving is a commonly used term to describe an intense desire for a substance or behaviour; however, its underlying neurobiology is not fully characterized. We have successfully used a cue exposure paradigm with functional neuro-imaging (H2 15O PET; PET, positron emission tomography) in abstinent opiate addicts. This study showed that salient cue exposure results in activation in the left anterior cingulate/mediofrontal cortex and elicited craving correlated with activity in the left orbitofrontal cortex. We therefore aimed to replicate this study in alcohol dependence to see if a similar pattern of neural activation occurred. We recruited six abstinent alcohol-dependent and six non-dependent subjects who each underwent a 12-run PET scan using H2 15O to measure changes in regional blood flow during exposure to an alcoholic drink or its visually matched non-alcoholic drink. Physiological data and subjective ratings were also recorded. Statistical parametric mapping (SPM99) was used to analyse the PET images. Compared with control subjects, abstinent alcohol-dependent subjects rated their alcohol craving higher at baseline and throughout the study, but there was no significant change in the scores in response to the cues in either group. SPM analysis across all subjects showed significant activation in the occipital cortex in response to the alcohol cue as compared with the neutral one. Analysis of the same regions that were activated in the opiate study, revealed significant increases in signal activation in the left medial prefrontal area, but only in abstinent alcohol-dependent subjects. In conclusion, in abstinent alcohol dependence we suggest that a simple cue exposure paradigm is not sufficiently powerful in functional imaging studies to determine the underlying neurobiology of subjective craving. Comparisons with the finding in opiate dependence suggest a shared region, the anterior cingulate/left medial prefrontal cortex is involved in the cue response in dependent subjects but not controls.

IS THERE COGNITIVE IMPAIRMENT IN CLINICALLY ‘HEALTHY’ ABSTINENT ALCOHOL DEPENDENCE?

The aim of this study was to determine neuropsychological performance in apparently cognitively, mentally, and physically healthy abstinent alcohol-dependent subjects compared with control subjects who were recruited for a number of different neuroimaging studies. All subjects completed a battery of neuropsychological tests as part of the neuroimaging protocol. The group dependent on alcohol performed as well as controls on a non-verbal memory test and verbal fluency but performed worse in the verbal memory task, Trail A + B, and total IQ derived from Silverstein's short-form of the WAIS-R. However, the IQ performance of both groups was above average. In both groups, age was associated with slower performance on the Trail A + B task. In the alcohol-dependent group, severity of dependence and length of abstinence was not associated with performance of any task. In this apparently clinically healthy population of abstinent alcohol-dependent subjects, frontal lobe dysfunction was detectable using the Trail A + B and digit symbol tasks. This was despite above-average WAIS-R IQ scores. Consideration needs to be given to routine incorporation of cognitive testing in alcohol dependence since subtle deficits may not be easily apparent and may impact on treatment outcome.