The Arf6 activator Efa6/PSD3 confers regional specificity and modulates ethanol consumption in Drosophila and humans.

Ubiquitously expressed genes have been implicated in a variety of specific behaviors, including responses to ethanol. However, the mechanisms that confer this behavioral specificity have remained elusive. Previously, we showed that the ubiquitously expressed small GTPase Arf6 is required for normal ethanol-induced sedation in adult Drosophila. Here, we show that this behavioral response also requires Efa6, one of (at least) three Drosophila Arf6 guanine exchange factors. Ethanol-naive Arf6 and Efa6 mutants were sensitive to ethanol-induced sedation and lacked rapid tolerance upon re-exposure to ethanol, when compared with wild-type flies. In contrast to wild-type flies, both Arf6 and Efa6 mutants preferred alcohol-containing food without prior ethanol experience. An analysis of the human ortholog of Arf6 and orthologs of Efa6 (PSD1-4) revealed that the minor G allele of single nucleotide polymorphism (SNP) rs13265422 in PSD3, as well as a haplotype containing rs13265422, was associated with an increased frequency of drinking and binge drinking episodes in adolescents. The same haplotype was also associated with increased alcohol dependence in an independent European cohort. Unlike the ubiquitously expressed human Arf6 GTPase, PSD3 localization is restricted to the brain, particularly the prefrontal cortex (PFC). Functional magnetic resonance imaging revealed that the same PSD3 haplotype was also associated with a differential functional magnetic resonance imaging signal in the PFC during a Go/No-Go task, which engages PFC-mediated executive control. Our translational analysis, therefore, suggests that PSD3 confers regional specificity to ubiquitous Arf6 in the PFC to modulate human alcohol-drinking behaviors.

EFhd2/Swiprosin-1 is a common genetic determinator for sensation-seeking/low anxiety and alcohol addiction.

In many societies, the majority of adults regularly consume alcohol. However, only a small proportion develops alcohol addiction. Individuals at risk often show a high sensation-seeking/low-anxiety behavioural phenotype. Here we asked which role EF hand domain containing 2 (EFhd2; Swiprosin-1) plays in the control of alcohol addiction-associated behaviours. EFhd2 knockout (KO) mice drink more alcohol than controls and spontaneously escalate their consumption. This coincided with a sensation-seeking and low-anxiety phenotype. A reversal of the behavioural phenotype with ß-carboline, an anxiogenic inverse benzodiazepine receptor agonist, normalized alcohol preference in EFhd2 KO mice, demonstrating an EFhd2-driven relationship between personality traits and alcohol preference. These findings were confirmed in a human sample where we observed a positive association of the EFhd2 single-nucleotide polymorphism rs112146896 with lifetime drinking and a negative association with anxiety in healthy adolescents. The lack of EFhd2 reduced extracellular dopamine levels in the brain, but enhanced responses to alcohol. In confirmation, gene expression analysis revealed reduced tyrosine hydroxylase expression and the regulation of genes involved in cortex development, Eomes and Pax6, in EFhd2 KO cortices. These findings were corroborated in Xenopus tadpoles by EFhd2 knockdown. Magnetic resonance imaging (MRI) in mice showed that a lack of EFhd2 reduces cortical volume in adults. Moreover, human MRI confirmed the negative association between lifetime alcohol drinking and superior frontal gyrus volume. We propose that EFhd2 is a conserved resilience factor against alcohol consumption and its escalation, working through Pax6/Eomes. Reduced EFhd2 function induces high-risk personality traits of sensation-seeking/low anxiety associated with enhanced alcohol consumption, which may be related to cortex function.

Decoding diagnosis and lifetime consumption in alcohol dependence from grey-matter pattern information.

OBJECTIVE: We investigated the potential of computer-based models to decode diagnosis and lifetime consumption in alcohol dependence (AD) from grey-matter pattern information. As machine-learning approaches to psychiatric neuroimaging have recently come under scrutiny due to unclear generalization and the opacity of algorithms, our investigation aimed to address a number of methodological criticisms. METHOD: Participants were adult individuals diagnosed with AD (N = 119) and substance-naïve controls (N = 97) ages 20-65 who underwent structural MRI. Machine-learning models were applied to predict diagnosis and lifetime alcohol consumption. RESULTS: A classification scheme based on regional grey matter attained 74% diagnostic accuracy and predicted lifetime consumption with high accuracy (r = 0.56, P < 10-10 ). A key advantage of the classification scheme was its algorithmic transparency, revealing cingulate, insular and inferior frontal cortices as important brain areas underlying classification. Validation of the classification scheme on data of an independent trial was successful with nearly identical accuracy, addressing the concern of generalization. Finally, compared to a blinded radiologist, computer-based classification showed higher accuracy and sensitivity, reduced age and gender biases, but lower specificity. CONCLUSION: Computer-based models applied to whole-brain grey-matter predicted diagnosis and lifetime consumption in AD with good accuracy. Computer-based classification may be particularly suited as a screening tool with high sensitivity.

[Schizophrenia and bipolar disorder : Treatment of cognitive impairments]. / Schizophrenie und bipolare Störung : Behandlung kognitiver Beeinträchtigungen.

More than half of the patients diagnosed with schizophrenia and a subgroup of patients diagnosed with bipolar disorder show impairment in neurocognitive and social cognitive performance. The degree of impairment varies from person to person. An improvement of cognitive impairment results in increased subjective quality of life and increased psychosocial functioning, to a much greater extent than successful treatment of other symptoms. Therefore, it is reasonable to not only recognize and bear decreased cognitive functioning in mind but also to offer specific treatment of impairments. The systematic review article in hand provides an overview of practice relevant treatment options in this respect. At present, cognitive remediation therapy shows the best treatment results, although only with moderate effect sizes. Physical activity can also be considered beneficial, even with the smaller number of studies available. Specific psychopharmacotherapy and non-invasive neurostimulation are still being assessed in clinical trials but show a promising perspective. Even though there are various beneficial treatment options to improve cognitive impairment potentially apparent in schizophrenia and bipolar disorder, future research will hopefully bring about even more effective interventions.

Genomic architecture of human neuroanatomical diversity.

Human brain anatomy is strikingly diverse and highly inheritable: genetic factors may explain up to 80% of its variability. Prior studies have tried to detect genetic variants with a large effect on neuroanatomical diversity, but those currently identified account for <5% of the variance. Here, based on our analyses of neuroimaging and whole-genome genotyping data from 1765 subjects, we show that up to 54% of this heritability is captured by large numbers of single-nucleotide polymorphisms of small-effect spread throughout the genome, especially within genes and close regulatory regions. The genetic bases of neuroanatomical diversity appear to be relatively independent of those of body size (height), but shared with those of verbal intelligence scores. The study of this genomic architecture should help us better understand brain evolution and disease.

Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents.

Despite the recognition that cortical thickness is heritable and correlates with intellectual ability in children and adolescents, the genes contributing to individual differences in these traits remain unknown. We conducted a large-scale association study in 1583 adolescents to identify genes affecting cortical thickness. Single-nucleotide polymorphisms (SNPs; n=54,837) within genes whose expression changed between stages of growth and differentiation of a human neural stem cell line were selected for association analyses with average cortical thickness. We identified a variant, rs7171755, associating with thinner cortex in the left hemisphere (P=1.12 × 10(-)(7)), particularly in the frontal and temporal lobes. Localized effects of this SNP on cortical thickness differently affected verbal and nonverbal intellectual abilities. The rs7171755 polymorphism acted in cis to affect expression in the human brain of the synaptic cell adhesion glycoprotein-encoding gene NPTN. We also found that cortical thickness and NPTN expression were on average higher in the right hemisphere, suggesting that asymmetric NPTN expression may render the left hemisphere more sensitive to the effects of NPTN mutations, accounting for the lateralized effect of rs7171755 found in our study. Altogether, our findings support a potential role for regional synaptic dysfunctions in forms of intellectual deficits.

Temporal delay discounting in acutely ill and weight-recovered patients with anorexia nervosa.

BACKGROUND: Patients with anorexia nervosa (AN) are characterized by a very low body weight but readily give up immediate rewards (food) for long-term goals (slim figure), which might indicate an unusual level of self-control. This everyday clinical observation may be quantifiable in the framework of the anticipation-discounting dilemma. METHOD: Using a cross-sectional design, this study compared the capacity to delay reward in 34 patients suffering from acute AN (acAN), 33 weight-recovered AN patients (recAN) and 54 healthy controls. We also used a longitudinal study to reassess 21 acAN patients after short-term weight restoration. A validated intertemporal choice task and a hyperbolic model were used to estimate temporal discounting rates. RESULTS: Confirming the validity of the task used, decreased delay discounting was associated with age and low self-reported impulsivity. However, no group differences in key measures of temporal discounting of monetary rewards were found. CONCLUSIONS: Increased cognitive control, which has been suggested as a key characteristic of AN, does not seem to extend the capacity to wait for delayed monetary rewards. Differences between our study and the only previous study reporting decreased delay discounting in adult AN patients may be explained by the different age range and chronicity of acute patients, but the fact that weight recovery was not associated with changes in discount rates suggests that discounting behavior is not a trait marker in AN. Future studies using paradigms with disorder-specific stimuli may help to clarify the role of delay discounting in AN.

White-matter microstructure and gray-matter volumes in adolescents with subthreshold bipolar symptoms.

Abnormalities in white-matter (WM) microstructure, as lower fractional anisotropy (FA), have been reported in adolescent-onset bipolar disorder and in youth at familial risk for bipolarity. We sought to determine whether healthy adolescents with subthreshold bipolar symptoms (SBP) would have early WM microstructural alterations and whether those alterations would be associated with differences in gray-matter (GM) volumes. Forty-two adolescents with three core manic symptoms and no psychiatric diagnosis, and 126 adolescents matched by age and sex, with no psychiatric diagnosis or symptoms, were identified after screening the IMAGEN database of 2223 young adolescents recruited from the general population. After image quality control, voxel-wise statistics were performed on the diffusion parameters using tract-based spatial statistics in 25 SBP adolescents and 77 controls, and on GM and WM images using voxel-based morphometry in 30 SBP adolescents and 106 controls. As compared with healthy controls, adolescents with SBP displayed lower FA values in a number of WM tracts, particularly in the corpus callosum, cingulum, bilateral superior and inferior longitudinal fasciculi, uncinate fasciculi and corticospinal tracts. Radial diffusivity was mainly higher in posterior parts of bilateral superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi and right cingulum. As compared with controls, SBP adolescents had lower GM volume in the left anterior cingulate region. This is the first study to investigate WM microstructure and GM morphometric variations in adolescents with SBP. The widespread FA alterations in association and projection tracts, associated with GM changes in regions involved in mood disorders, suggest altered structural connectivity in those adolescents.

Cortical thickness of superior frontal cortex predicts impulsiveness and perceptual reasoning in adolescence.

Impulsiveness is a pivotal personality trait representing a core domain in all major personality inventories. Recently, impulsiveness has been identified as an important modulator of cognitive processing, particularly in tasks that require the processing of large amounts of information. Although brain imaging studies have implicated the prefrontal cortex to be a common underlying representation of impulsiveness and related cognitive functioning, to date a fine-grain and detailed morphometric analysis has not been carried out. On the basis of ahigh-resolution magnetic resonance scans acquired in 1620 healthy adolescents (IMAGEN), the individual cortical thickness (CT) was estimated. Correlations between Cloninger's impulsiveness and CT were studied in an entire cortex analysis. The cluster identified was tested for associations with performance in perceptual reasoning tasks of the Wechsler Intelligence Scale for Children (WISC IV). We observed a significant inverse correlation between trait impulsiveness and CT of the left superior frontal cortex (SFC; Monte Carlo Simulation P<0.01). CT within this cluster correlated with perceptual reasoning scores (Bonferroni corrected) of the WISC IV. On the basis of a large sample of adolescents, we identified an extended area in the SFC as a correlate of impulsiveness, which appears to be in line with the trait character of this prominent personality facet. The association of SFC thickness with perceptual reasoning argues for a common neurobiological basis of personality and specific cognitive domains comprising attention, spatial reasoning and response selection. The results may facilitate the understanding of the role of impulsiveness in several psychiatric disorders associated with prefrontal dysfunctions and cognitive deficits.

Dopamine-modulated aversive emotion processing fails in alcohol-dependent patients.

Negative mood states after alcohol detoxification may enhance the relapse risk. As recently shown in healthy volunteers, dopamine storage capacity (V d) in the left amygdala was positively correlated with functional activation in the left amygdala and anterior cingulate cortex (ACC) during an emotional task; high functional connectivity between the amygdala and the ACC, a region important for emotion regulation, was associated with low trait anxiety. Based on these findings, we now tested whether detoxified alcohol-dependent patients have a disrupted modulation of the anterior cingulate cortex activation in response to aversive stimuli by amygdala dopamine. Furthermore, we asked whether disrupted functional coupling between amygdala and ACC during aversive processing is related to trait anxiety.We used combined 6-[18F]-fluoro-l-DOPA positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and Spielberger's state-trait anxiety questionnaire (STAI) in 11 male detoxified alcohol-dependent patients compared to 13 matched healthy controls.Unlike healthy controls, patients showed no significant correlation between our PET metric for dopamine storage capacity (FDOPA V d), in left amygdala and activation in left ACC. Moreover, the functional connectivity between amygdala and ACC during processing of aversive emotional stimuli was reduced in patients. Voxel-based morphometry did not reveal any discernible group differences in amygdala volume.These results suggest that dopamine-modulated corticolimbic circuit function is important for responding to emotional information such that apparent functional deficits in this neuromodulatory circuitry may contribute to trait anxiety in alcohol-dependent patients.

The personality trait self-directedness predicts the amygdala's reaction to appetizing cues in fMRI.

Personality and neural response to food cues in various mesolimbic brain structures have been linked to eating disorders. We investigated the question of whether personality traits in healthy individuals correlate with the brain activation induced on confrontation with appetizing visual stimuli. Personality was assessed in 27 normal-weight participants (14 women, mean age=26.0, SD=3.3 years) with the Temperament and Character Inventory (TCI). After an overnight fast, participants viewed blocks of pictures, half containing appetizing food and the other half showing scrambled pictures as control. After each block, participants rated their appetite. Brain activation was measured using a 3T MR scanner. Food compared to control stimuli elicited a significantly higher appetite rating, as well as strong activation in the ventral and dorsal visual stream, the fusiform gyrus and consecutive limbic centres such as the parahippocampal gyrus, the amygdala, the thalamus, the insula, the ventral striatum and the orbitofrontal cortex. In a region-of-interest analysis, the TCI trait self-directedness was negatively correlated with mean blood oxygenation level dependent (BOLD) signal change in the right amygdala (r=-.43, p=.025). Ultimately, amygdala reactivity might provide a risk factor for the development of eating disorders.

L-DOPA administration shifts the stability-flexibility balance towards attentional capture by distractors during a visual search task.

RATIONALE: The cognitive control dilemma describes the necessity to balance two antagonistic modes of attention: stability and flexibility. Stability refers to goal-directed thought, feeling, or action and flexibility refers to the complementary ability to adapt to an ever-changing environment. Their balance is thought to be maintained by neurotransmitters such as dopamine, most likely in a U-shaped rather than linear manner. However, in humans, studies on the stability-flexibility balance using a dopaminergic agent and/or measurement of brain dopamine are scarce. OBJECTIVE: The study aimed to investigate the causal involvement of dopamine in the stability-flexibility balance and the nature of this relationship in humans. METHODS: Distractibility was assessed as the difference in reaction time (RT) between distractor and non-distractor trials in a visual search task. In a randomized, placebo-controlled, double-blind, crossover study, 65 healthy participants performed the task under placebo and a dopamine precursor (L-DOPA). Using 18F-DOPA-PET, dopamine availability in the striatum was examined at baseline to investigate its relationship to the RT distractor effect and to the L-DOPA-induced change of the RT distractor effect. RESULTS: There was a pronounced RT distractor effect in the placebo session that increased under L-DOPA. Neither the RT distractor effect in the placebo session nor the magnitude of its L-DOPA-induced increase were related to baseline striatal dopamine. CONCLUSIONS: L-DOPA administration shifted the stability-flexibility balance towards attentional capture by distractors, suggesting causal involvement of dopamine. This finding is consistent with current theories of prefrontal cortex dopamine function. Current data can neither confirm nor falsify the inverted U-shaped function hypothesis with regard to cognitive control.

Boys do it the right way: sex-dependent amygdala lateralization during face processing in adolescents.

Previous studies have observed a sex-dependent lateralization of amygdala activation related to emotional memory. Specifically, it was shown that the activity of the right amygdala correlates significantly stronger with memory for images judged as arousing in men than in women, and that there is a significantly stronger relationship in women than in men between activity of the left amygdala and memory for arousing images. Using a large sample of 235 male adolescents and 235 females matched for age and handedness, we investigated the sex-specific lateralization of amygdala activation during an emotional face perception fMRI task. Performing a formal sex by hemisphere analysis, we observed in males a significantly stronger right amygdala activation as compared to females. Our results indicate that adolescents display a sex-dependent lateralization of amygdala activation that is also present in basic processes of emotional perception. This finding suggests a sex-dependent development of human emotion processing and may further implicate possible etiological pathways for mental disorders most frequent in adolescent males (i.e., conduct disorder).

Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate.

In alcoholism, both relapse to alcohol drinking and treatment response are suggested to be genetically modulated. This study set out to determine whether the top 15 single nucleotide polymorphisms (SNPs) of a recent genome-wide association (GWA) and follow-up study of alcohol dependence are associated with relapse behavior and pharmacological treatment response in 374 alcohol-dependent subjects who underwent a randomized, double-blind, placebo-controlled trial with acamprosate, naltrexone or placebo. The single nucleotide polymorphism, rs13273672, an intronic SNP in the gene for GATA-binding protein 4 (GATA4), was associated with relapse within the 90-day medical treatment period (P<0.01). Subsequent pharmacogenetic analyses showed that this association was mainly based on patients treated with acamprosate (P<0.01). In line with the observation that natriuretic peptide promoters are modulated by GATA4, a significant gene dose effect on the variance of atrial natriuretic peptide (ANP) plasma concentration in the different GATA4 genotypes (P<0.01) was found. Hence, genetic variations in GATA4 might influence relapse and treatment response to acamprosate in alcohol-dependent patients via modulation of ANP plasma levels. These results could help to identify those alcohol-dependent patients who may be at an increased risk of relapse and who may better respond to treatment with acamprosate.

Acute alcohol does not impair attentional inhibition as measured with Stroop interference scores but impairs Stroop performance.

RATIONALE: Inhibition is a core executive function and refers to the ability to deliberately suppress attention, behavior, thoughts, and/or emotions and instead act in a specific manner. While acute alcohol exposure has been shown to impair response inhibition in the stop-signal and Go/NoGo tasks, reported alcohol effects on attentional inhibition in the Stroop task are inconsistent. Notably, studies have operationalized attentional inhibition variably and there has been intra- and inter-individual variability in alcohol exposure. OBJECTIVE: This study aimed to examine the acute effects of alcohol on attentional inhibition, considering previous limitations. METHODS: In a single-blind, cross-over design, 40 non-dependent participants with a medium-to-high risk drinking behavior performed a Counting Stroop task (CST) under a baseline and an arterial blood alcohol concentration (aBAC) clamp at 80 mg%. Attentional inhibition was assessed as the alteration of reaction times (RT), error rates (ER), and inverse efficiency scores (IES) between incongruent and congruent trials (interference score). Stroop performance was also assessed regardless of trial-type. RESULTS: Compared to saline, acute alcohol exposure via an aBAC clamp did not affect CST interference scores but increased RTs and IES in both incongruent and congruent trials. CONCLUSIONS: Attentional inhibition (Stroop interference score) was not impaired by clamped moderate alcohol exposure. Acute alcohol impaired Stroop performance evidenced by a general increase in response times. Our findings suggest that response and attentional inhibition do not share the same neurocognitive mechanisms and are affected differently by alcohol. Results could also be explained by automated behaviors known to be relatively unaffected by acute alcohol.

Empathy and the ability to experience one's own emotions modify the expression of blatant and subtle prejudice among young male adults.

Prejudices can lead to discrimination, social exclusion, and violence particularly among young male adults. Previous findings suggest that the degree of holding prejudices is linked to low levels of empathy, while low levels of empathy have been associated with alexithymia, the inability to experience one's own feelings. We tested the hypothesis that the impact of a lack of empathy on reporting blatant and subtle prejudices is moderated by the inability to identify one's own feelings. In a sample of n = 136 young male adults aged 21 years (mean = 21.5 years; sd = 0.3), we conducted correlation and moderator analyses to determine possible relationships between prejudices, empathy, and alexithymia as assessed by self-report questionnaires. Prejudices were assessed by the Blatant and Subtle Prejudice Scale (BSPS), empathy was assessed by the German modified version of the Interpersonal Reactivity Index (IRI), and alexithymia by the 20-item Toronto Alexithymia Scale (TAS-20). Self-reported empathy levels were correlated with the strength of subtle and blatant prejudices. The moderation analyses revealed that the negative association between empathy and subtle prejudice increased with decreasing alexithymia. The negative association between empathy and blatant prejudice, on the other hand, was significant only for participants with low levels of alexithymia. These results suggest that empathy can limit the expression of blatant and to some degree also subtle prejudice when subjects are capable to identify their own feelings in a group of young males.

Anxiety is associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major depression: a [11C]DASB PET study.

Serotonergic dysfunction may contribute to negative mood states in affective disorders. Some in vivo imaging studies showed reduced availability of serotonin transporters (5-HTT) in the brainstem and thalamus of patients with major depression. We tested the hypothesis that 5-HTT availability is reduced in unmedicated unipolar patients with major depression compared to healthy control subjects matched for gender, age, genotype and smoking status. Availability of 5-HTT was measured in vivo with positron emission tomography and [(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB) in the midbrain, thalamus and amygdala. DASB binding was correlated with the severity of depression (Beck's Depression Inventory), anxiety (Spielberger's State-Trait Anxiety Inventory) and personality traits (Temperament and Character Inventory). Patients with major depression displayed reduced 5-HTT availability in the thalamus (P=0.005). In patients, low serotonin transporter availability correlated with high anxiety (thalamus: r=-0.78, P=0.004; midbrain: r=-0.78, P=0.004; amygdala: r=-0.80, P=0.003). Correlations with severity of depression were weaker and did not survive correction for multiple testing. These results support the hypothesis that central serotonergic dysfunction is associated with negative mood states in affective disorders. In the thalamus, a low serotonin reuptake capacity may interfere with thalamic control of cortical excitability and contribute to anxiety rather than depression per se in major depression.

Interaction between striatal volume and DAT1 polymorphism predicts working memory development during adolescence.

There is considerable inter-individual variability in the rate at which working memory (WM) develops during childhood and adolescence, but the neural and genetic basis for these differences are poorly understood. Dopamine-related genes, striatal activation and morphology have been associated with increased WM capacity after training. Here we tested the hypothesis that these factors would also explain some of the inter-individual differences in the rate of WM development. We measured WM performance in 487 healthy subjects twice: at age 14 and 19. At age 14 subjects underwent a structural MRI scan, and genotyping of five single nucleotide polymorphisms (SNPs) in or close to the dopamine genes DRD2, DAT-1 and COMT, which have previously been associated with gains in WM after WM training. We then analyzed which biological factors predicted the rate of increase in WM between ages 14 and 19. We found a significant interaction between putamen size and DAT1/SLC6A3 rs40184 polymorphism, such that TC heterozygotes with a larger putamen at age 14 showed greater WM improvement at age 19. The effect of the DAT1 polymorphism on WM development was exerted in interaction with striatal morphology. These results suggest that development of WM partially share neuro-physiological mechanism with training-induced plasticity.

Strong seduction: impulsivity and the impact of contextual cues on instrumental behavior in alcohol dependence.

Alcohol-related cues acquire incentive salience through Pavlovian conditioning and then can markedly affect instrumental behavior of alcohol-dependent patients to promote relapse. However, it is unclear whether similar effects occur with alcohol-unrelated cues. We tested 116 early-abstinent alcohol-dependent patients and 91 healthy controls who completed a delay discounting task to assess choice impulsivity, and a Pavlovian-to-instrumental transfer (PIT) paradigm employing both alcohol-unrelated and alcohol-related stimuli. To modify instrumental choice behavior, we tiled the background of the computer screen either with conditioned stimuli (CS) previously generated by pairing abstract pictures with pictures indicating monetary gains or losses, or with pictures displaying alcohol or water beverages. CS paired to money gains and losses affected instrumental choices differently. This PIT effect was significantly more pronounced in patients compared to controls, and the group difference was mainly driven by highly impulsive patients. The PIT effect was particularly strong in trials in which the instrumental stimulus required inhibition of instrumental response behavior and the background CS was associated to monetary gains. Under that condition, patients performed inappropriate approach behavior, contrary to their previously formed behavioral intention. Surprisingly, the effect of alcohol and water pictures as background stimuli resembled that of aversive and appetitive CS, respectively. These findings suggest that positively valenced background CS can provoke dysfunctional instrumental approach behavior in impulsive alcohol-dependent patients. Consequently, in real life they might be easily seduced by environmental cues to engage in actions thwarting their long-term goals. Such behaviors may include, but are not limited to, approaching alcohol.

Galantamine reduces smoking in alcohol-dependent patients: a randomized, placebo-controlled trial.

INTRODUCTION: The high morbidity and mortality caused by smoking highlights the importance of investigating new strategies for smoking cessation or reduction. Galantamine is an acetylcholinesterase inhibitor that increases the effect of acetylcholine (ACh). The nicotinic ACh receptor is activated via positive allosteric modulation (APL). METHODS: We investigated whether galantamine reduces smoking by performing a 24-week randomized, placebo-controlled, multicentric clinical trial in recently detoxified alcohol-dependent patients. We included all study subjects irrespective of an intention or motivation to abstain from nicotine. Specific treatment for cessation or reduction of smoking was not provided. Smoking behavior was assessed by means of patients' diaries. The nicotine metabolite cotinine was measured to verify the number of smoked cigarettes as documented in the patient's diary. RESULTS: 114 randomized smokers received galantamine (n = 56) or placebo (n = 58) for 12 weeks. Follow-up examinations were terminated after an additional 12 weeks without treatment. Smoking behavior did not differ between both groups at baseline. After treatment, the intention-to-treat analysis revealed significant differences with a 20% lower cumulative number of smoked cigarettes and a 15% lower number of smoking days in the galantamine group compared to placebo. The average number of smoked cigarettes per smoking day as well as the cotinine values decreased about 10%. Cotinine values showed a positive correlation with the number of documented cigarettes, validating the patients' diaries. CONCLUSION: Our tentative data indicate that galantamine reduces smoking behavior even without any additional specific intervention. We suggest introducing the term "substitution therapy" into the treatment of smoking. This result could open up a new treatment approach for groups of patients which usually have a low motivation for change.