A.F.A. Schellekens

Establishing the Dopamine Dependency of Human Striatal Signals During Reward and Punishment Reversal Learning

Drugs that alter dopamine transmission have opposite effects on reward and punishment learning. These opposite effects have been suggested to depend on dopamine in the striatum. Here, we establish for the first time the neurochemical specificity of such drug effects, during reward and punishment learning in humans, by adopting a coadministration design. Participants (N = 22) were scanned on 4 occasions using functional magnetic resonance imaging, following intake of placebo, bromocriptine (dopamine-receptor agonist), sulpiride (dopamine-receptor antagonist), or a combination of both drugs. A reversal-learning task was employed, in which both unexpected rewards and punishments signaled reversals. Drug effects were stratified with baseline working memory to take into account individual variations in drug response. Sulpiride induced parallel span-dependent changes on striatal blood oxygen level-dependent (BOLD) signal during unexpected rewards and punishments. These drug effects were found to be partially dopamine-dependent, as they were blocked by coadministration with bromocriptine. In contrast, sulpiride elicited opposite effects on behavioral measures of reward and punishment learning. Moreover, sulpiride-induced increases in striatal BOLD signal during both outcomes were associated with behavioral improvement in reward versus punishment learning. These results provide a strong support for current theories, suggesting that drug effects on reward and punishment learning are mediated via striatal dopamine.

Disruption of Reward Processing in Addiction : An Image-Based Meta-analysis of Functional Magnetic Resonance Imaging Studies

Importance Disrupted reward processing, mainly driven by striatal dysfunction, is a key characteristic of addictive behaviors. However, functional magnetic resonance imaging (fMRI) studies have reported conflicting results, with both hypoactivations and hyperactivations during anticipation and outcome notification of monetary rewards in addiction. Objective To determine the nature and direction of reward-processing disruptions during anticipation and outcome notification of monetary rewards in individuals with addiction using image-based meta-analyses of fMRI studies. Data Sources Relevant publications were identified searching PubMed (inclusion until March 2015) using the following terms: reward, fMRI, substance use, cocaine, cannabis, opiates, alcohol, nicotine, smokers, gambling, gamblers, gaming, and gamers. Authors of included articles were contacted to obtain statistical fMRI maps. Study Selection Inclusion criteria: reward task involving monetary reward anticipation and/or outcome; participants showing addictive behaviors; and healthy control group. Exclusion criteria: participants aged younger than 18 years; recreational substance use or gambling; participants at risk for addictive behaviors; and studies using the same patient data as other included studies. Data Extraction and Synthesis Study procedures were conducted in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines. Using Seed-based d Mapping software, meta-analyses were performed using random-effect nonparametric statistics with group whole brain T-maps from individual studies as input. Analyses were performed across all addictions and for substance and gambling addictions separately. Main Outcomes and Measures Group differences (individuals with addiction vs control individuals) in reward-related brain activation during reward anticipation and outcome using fMRI (planned before data collection). Results Twenty-five studies were included in the meta-analysis, representing 643 individuals with addictive behaviors and 609 healthy control individuals. During reward anticipation, individuals with substance and gambling addictions showed decreased striatal activation compared with healthy control individuals. During reward outcome, individuals with substance addiction showed increased activation in the ventral striatum, whereas individuals with gambling addiction showed decreased activation in the dorsal striatum compared with healthy control individuals. Conclusions and Relevance Striatal hypoactivation in individuals with addiction during reward anticipation and in individuals with gambling addiction during reward outcome is in line with the reward-deficiency theory of addiction. However, the combination of hypoactivation during reward anticipation and hyperactivation during reward outcome in the striatum of individuals with substance addiction may be explained using learning-deficit theory.

Alcohol dependence and anxiety increase error-related brain activity

AIMS Detection of errors is crucial for efficient goal-directed behaviour. The ability to monitor behaviour is found to be diminished in patients with substance dependence, as reflected in decreased error-related brain activity, i.e. error-related negativity (ERN). The ERN is also decreased in other psychiatric disorders with impaired response inhibition, such as attention-deficit hyperactivity disorder and borderline personality disorder, but increased in anxiety disorders. The objective of the current study was to assess error monitoring in alcohol-dependent patients in relation to psychiatric comorbidity. We expected decreased error monitoring in alcohol-dependent patients with impulse control disorders and increased error monitoring in anxious alcohol-dependent patients. DESIGN In a case-control design alcohol-dependent patients were compared with healthy controls. SETTING AND PARTICIPANTS A consecutive series of 29 male alcohol-dependent patients, between 18 and 55 years of age, applying for in-patient detoxification were recruited at Novadic Kentron Center for Addiction Treatment. Fifteen age-matched healthy controls were recruited through advertisements in regional newspapers. MEASUREMENTS Event-related potentials were recorded while performing a speeded choice-reaction task, from which ERN amplitudes were calculated. Axis-I and -II psychiatric comorbidity were assessed using the MINI International Neuropsychiatric Interview and the Structured Interview for DSM-IV Personality disorders. All participants completed the Temperament and Character Inventory and Profile of Mood States. FINDINGS ERN amplitudes were increased for alcohol-dependent patients compared to healthy controls, particularly in patients with comorbid anxiety disorders. CONCLUSIONS Increased error monitoring in alcohol-dependent patients, particularly those with comorbid anxiety disorders, is in contrast with previous studies that suggested decreased error monitoring to be a general feature in substance use disorders. Psychiatric disorders co-occurring with alcohol dependence, such as anxiety disorders, may indicate subpopulations of alcohol-dependent patients, with distinct neurobiological and genetic characteristics, possibly requiring different treatment strategies.

COMT Val158Met modulates the effect of childhood adverse experiences on the risk of alcohol dependence.

Genetic factors and childhood adverse experiences contribute to the vulnerability to alcohol dependence. However, empirical data on the interplay between specific genes and adverse experiences are few. The COMT Val158Met and DRD2/ANKK1 Taq1A genotypes have been suggested to affect both stress sensitivity and the risk for alcohol dependence. This study tested the hypothesis that genetic variation in COMT Val158Met and DRD2/ANKK1 Taq1A interacts with childhood adverse experiences to predict alcohol dependence. Male abstinent alcohol‐dependent patients (n = 110) and age‐matched healthy male controls (n = 99) were genotyped for the COMT Val158Met and the DRD2/ANKK1 Taq1A genotypes. Childhood adverse events were measured using three self‐report questionnaires. Alcohol dependence severity, age of onset and duration of alcohol dependence were analyzed as secondary outcome measures. Statistical analysis involved logistic regression analysis and analysis of variance. Alcohol‐dependent patients reported increased childhood adversity. The interaction between childhood adversity and the COMT Val158Met genotype added significantly to the prediction model. This gene–environment interaction was confirmed in the analysis of the secondary outcome measures, i.e. alcohol dependence severity, age of onset and duration of alcohol dependence. The DRD2/ANKK1 Taq1A genotype was not related to alcohol dependence, nor did it interact with childhood adversity in predicting alcohol dependence. This study provides evidence for a gene–environment interaction in alcohol dependence, in which an individuals sensitivity to childhood adverse experience is moderated by the COMT genotype. Exposed carriers of a low‐activity Met allele have a higher risk to develop severe alcohol dependence than individuals homozygous for the Val allele.

Reduced Dopamine Receptor Sensitivity as an Intermediate Phenotype in Alcohol Dependence and the Role of the COMT Val158Met and DRD2 Taq1A Genotypes

CONTEXT Alcohol dependence is a common neuropsychiatric disorder with high heritability. However, genetic association studies on alcohol dependence are often troubled by nonreplication. The use of intermediate phenotypes may help make clear the mode of action of various candidate genes and improve the reproducibility of genetic association studies. OBJECTIVE To test central dopamine receptor sensitivity as an intermediate phenotype for alcohol dependence, specifically evaluating the hypothesis that the dopaminergic genes COMT Val158Met and DRD2 Taq1A affect dopamine receptor sensitivity. DESIGN Case-control pharmacogenetic challenge study. SETTING Patients with alcohol dependence admitted for detoxification were compared with healthy control subjects matched for age and level of education. PARTICIPANTS Patients (n = 110) were a consecutive sample, whereas controls (n = 99) were recruited through advertisements in regional newspapers. INTERVENTION A dopamine challenge test was subcutaneously administered using the dopamine agonist apomorphine hydrochloride (0.005 mg/kg). MAIN OUTCOME MEASURES Outcome measures were plasma growth hormone levels and results of a continuous performance task. RESULTS Central dopamine receptor sensitivity is reduced in alcohol dependence, and this is modulated by dopaminergic genes. Specifically, DRD2 Taq1A genotype affected dopamine receptor sensitivity as measured by plasma growth hormone levels, and COMT Val158Met genotype affected dopamine receptor sensitivity as measured by performance on a continuous performance task. In a logistic regression analysis, reduced dopamine receptor sensitivity on both measures predicted alcohol dependence, without an additive effect of the COMT Val158Met and DRD2 Taq1A genotypes. CONCLUSIONS COMT Val158Met and DRD2 Taq1A may affect the intermediate phenotype of central dopamine receptor sensitivity. COMT Val158Met and DRD2 Taq1A may confer their risk of alcohol dependence through reduced dopamine receptor sensitivity in the prefrontal cortex and hindbrain, respectively.

The Level of Alexithymia in Alcohol-Dependent Patients Does Not Influence Outcomes after Inpatient Treatment

Background: The inability of individuals with Alcohol Use Disorders (AUD) to recognize and describe their feelings and cravings may be due to alexithymia. Previous researches have shown evidence for a negative influence of alexithymia on treatment outcomes in patients with AUD. Therefore, it was hypothesized that high alexithymic patients with AUD would benefit less from cognitive behavioral therapy (CBT) compared with low alexithymic patients. Methods: One hundred alcohol-dependent inpatients (DSM IV) were assessed with the Mini International Neuropsychiatric Interview for psychiatric disorders, the Toronto Alexithymia Scale (TAS-20), and the European Addiction Severity Index (EuropASI). Baseline alexithymia, as a categorical and continuous variable, was used to compare or relate baseline demographic and addiction characteristics, time in treatment, abstinence, and differences in addiction severity at 1-year follow-up. Analyses were performed using χ2 test, analysis of variance or Kruskal–Wallis, paired t-tests or Wilcoxon’s signed rank tests, multivariate logistic, and linear regression models, as appropriate. Results: The prevalence of high alexithymia (TAS-20 > 61) was 45%. The total TAS-20 score correlated negatively with years of education (r = −.21; p = .04) and positively with the psychiatry domain of the EuropASI (r = .23; p = .04). Alexithymia showed no relation to abstinence, time in treatment, or change in severity of alcohol-related problems on the EuropASI. Conclusion: High alexithymic patients with AUD do benefit equally from inpatient CBT-like treatment as low alexithymic patients with AUD. Scientific significance: Multimethod alexithymia assessments with an observer scale have been advised to judge the relationship with resulting outcome in CBT.

The dopamine agonist apomorphine differentially affects cognitive performance in alcohol dependent patients and healthy controls.

BACKGROUND Reduced metabolic activity in frontal brain regions, and reduced striatal dopamine receptor densities have been shown in alcohol dependent patients. Little is known on functional changes in the fronto-striatal-thalamic dopaminergic neurocircuitry in these patients. The objective of this study was to assess sensitivity of prefrontal dopamine receptors in alcohol dependent patients. EXPERIMENTAL PROCEDURES Male alcohol dependent patients (N=40) and healthy controls (N=39) performed an AX-continuous performance test before and after administration of the DA agonist apomorphine (0.005 mg/kg). RESULTS At baseline alcohol dependent patients were slower and less accurate compared to healthy controls. After administration of apomorphine, performance improved in alcohol dependent patients and deteriorated in healthy controls. CONCLUSIONS Reduced cognitive performance in alcohol dependent patients compared with healthy controls may indicate dopamine dysfunctioning at the prefrontal level. Improvement of cognitive performance in alcohol dependent patients after administration of apomorphine and deterioration in healthy controls provides evidence for an inverted U-shape relation between dopaminergic functioning and cognitive performance.

The role of the habenula in the transition from reward to misery in substance use and mood disorders

The habenula (Hb) is an evolutionary well-conserved structure located in the epithalamus. The Hb receives inputs from the septum, basal ganglia, hypothalamus, anterior cingulate and medial prefrontal cortex, and projects to several midbrain centers, most importantly the inhibitory rostromedial tegmental nucleus (RMTg) and the excitatory interpeduncular nucleus (IPN), which regulate the activity of midbrain monoaminergic nuclei. The Hb is postulated to play a key role in reward and aversion processing across species, including humans, and to be implicated in the different stages of transition from recreational drug intake to addiction and co-morbid mood disorders. The Hb is divided into two anatomically and functionally distinct nuclei, the lateral (LHb) and the medial (MHb), which are primarily involved in reward-seeking (LHb) and misery-fleeing (MHb) behavior by controlling the RMTg and IPN, respectively. This review provides a neuroanatomical description of the Hb, discusses preclinical and human findings regarding its role in the development of addiction and co-morbid mood disorders, and addresses future directions in this area.

Early-Onset Alcohol Dependence Increases the Acoustic Startle Reflex

BACKGROUND Hyperreactivity and impaired sensory gating of the acoustic startle response in alcohol dependence has been suggested to reflect a residual effect of previous detoxifications, increasing the severity of subsequent withdrawal episodes. Previous studies on the acoustic startle only included early-onset alcohol-dependent patients. The observed abnormalities may therefore also be specific for this subtype of alcohol dependence. We investigated the acoustic startle response in alcohol-dependent patients and healthy controls and hypothesized that (i) early-onset alcohol-dependent patients show increased acoustic startle responses compared with late-onset alcohol-dependent patients and healthy controls, and (ii) the duration of alcohol dependence or the number of prior detoxifications would not explain the differences in the acoustic startle between early- and late-onset alcohol dependence. METHODS The acoustic startle reflex was assessed in detoxified, male alcohol-dependent patients (N = 83) and age-matched healthy male controls (N = 86). Reflex eye blink responses to an auditory startle stimulus were measured by means of electromyographic recordings over the right orbicularis oculi muscle. Reflex amplitudes and levels of prepulse inhibition (PPI) were analyzed. RESULTS There was no association between number of previous withdrawals and the startle response or PPI. Early-onset alcohol-dependent patients showed higher acoustic startle amplitudes compared with late-onset alcohol-dependent patients and healthy controls [75/105 dB: F(2, 166) = 9.2, p < 0.001; 85/105 dB: F(2, 166) = 12.1, p < 0.001; 95 dB: F(2, 166) = 8.2, p < 0.001; 105 dB: F(2, 166) = 9.7, p < 0.001], and there were no differences in PPI. CONCLUSIONS Increased acoustic startle response in detoxified early-onset alcohol-dependent patients may reflect a trait marker specifically involved in early-onset alcohol dependence. The findings of the current study do not support the hypothesis that the increased startle response is a residual state marker.

Pharmacological Treatment in γ-Hydroxybutyrate (GHB) and γ-Butyrolactone (GBL) Dependence: Detoxification and Relapse Prevention

The misuse of γ-hydroxybutyrate (GHB) for recreational purposes has resulted in an increase in GHB-related problems such as intoxications, dependence and withdrawal in several countries in Europe, Australia and the US over the last decade. However, prevalence rates of misuse of GHB and its precursor, γ-butyrolactone (GBL), are still relatively low. In this qualitative review paper, after a short introduction on the pharmacology of GHB/GBL, followed by a summary of the epidemiology of GHB abuse, an overview of GHB dependence syndrome and GHB/GBL withdrawal syndrome is provided. Finally, the existing literature on management of GHB detoxification, both planned and unplanned, as well as the available management of GHB withdrawal syndrome, is summarized. Although no systematic studies on detoxification and management of withdrawal have been performed to date, general recommendations are given on pharmacological treatment and preferred treatment setting.