Epigenetic alteration of the dopamine transporter gene in alcohol-dependent patients is associated with age.

Chronic alcohol abuse and dependence are associated with dysfunctional dopaminergic neurotransmission in mesocorticolimbic circuits. Genetic and environmental factors have been shown to modulate susceptibility to alcohol dependence, and both may act through epigenetic mechanisms that can modulate gene expression, e.g. DNA methylation at CpG sites. Recent studies have suggested that DNA methylation patterns may change over time. However, few data are available concerning the rate of these changes in specific genes. A recent study found that hypermethylation of the promoter of the dopamine transporter (DAT) gene was positively correlated with alcohol dependence and negatively correlated with alcohol craving. The aim of the present study was to replicate these findings in a larger sample of alcohol-dependent patients and population-based controls matched for age and sex. No difference in methylation level was observed between patients and controls, and no difference in methylation level was observed before and after alcohol withdrawal in patients. However, patients with more severe craving showed a trend towards lower DAT methylation levels (P = 0.07), which is consistent with previous findings. Furthermore, in our overall sample, DAT methylation levels increased with age. Interestingly, a separate analysis of patients suggested that this finding was mainly driven by the patient group. Although the present data do not clarify whether chronic alcohol abuse is responsible for this phenomenon or merely enhances an ageing-specific process, our findings suggest that hypermethylation in alcohol-dependent patients is a consequence, rather than a cause, of the disorder.

Lack of association of a functional catechol-O-methyltransferase gene polymorphism with risk of tobacco smoking: results from a multicenter case-control study.

BACKGROUND: The catechol-O-methyltransferase (COMT) modulates dopaminergic neurotransmission in the prefrontal cortex as well as in the mesolimbic reward system. Since the reward system mediates addictive behavior, the COMT gene is a strong candidate gene regarding the pathophysiology of tobacco dependence and smoking behavior. Because of rather conflicting results in previous studies, the purpose of the present study was to test for association between a functional genetic variant in the COMT gene (single nucleotide polymorphism [SNP] rs4680) and tobacco smoking behavior. METHODS: In a population-based case-control multicenter study designed for tobacco addiction research, a total of 551 current smokers of European ancestry and 548 age-matched healthy volunteers (never-smokers) were genotyped for SNP rs4680 and extensively characterized concerning their smoking behavior. RESULTS: We found no association between smoking status and SNP rs4680 genotype nor did we find a significant association to the degree of tobacco dependence. CONCLUSIONS: Although prefrontal cortical and ventral striatal activity are highly relevant for addictive behavior, and under partial control of COMT rs4680 genotype, no association between COMT and smoking behavior was observed. Other genetic variants may account for the high heritability of behavioral smoking phenotypes.

Neurocognitive impairments in non-deprived smokers--results from a population-based multi-center study on smoking-related behavior.

The aim of the present study was to examine neurocognitive function associated with chronic nicotine use. A total of 2163 healthy participants (1002 smokers, 1161 never-smoking controls) participated in a population-based case-control design. The main outcome measures were six cognitive domain factors derived from a neuropsychological test battery. In smokers, the battery was administered after controlled smoking of one cigarette. Analyses included age, sex and education as covariates. Results demonstrated small, but significant deficits in smokers for visual attention (P<0.001) and cognitive impulsivity (P<0.006), while verbal episodic memory, verbal fluency, verbal working memory, and Stroop-interference did not differ between groups. These attention/impulsivity deficits were also present in smokers with only a low amount of cigarette consumption. Lifetime nicotine use (pack-years) was not correlated with cognition in smokers. In conclusion, this study confirmed subtle and specific cognitive deficits in non-deprived smokers. The independence of these deficits from consumption intensity may argue for an a priori deficit of some cognitive abilities in smokers. These specific deficits may constitute intermediate phenotypes for genetic research on nicotine use.

Functional polymorphism in the neuropeptide Y gene promoter (rs16147) is associated with serum leptin levels and waist-hip ratio in women.

OBJECTIVE: The neuropeptide-Y (NP-Y) gene is a strong candidate gene in the pathophysiology of obesity-linked behavior, and several single-nucleotide polymorphisms of NP-Y have already been linked to body weight and appetite. However, the results from current studies remain inconclusive. The aim of the present study was to test whether a certain functional genetic variant (SNP rs16147) in the NP-Y promoter gene is associated with serum leptin levels and body fat distribution. METHOD: We genotyped and measured the serum leptin levels of the NP-Y rs16147 polymorphism in 1,097 Caucasian subjects in the context of a population-based, case-control multicenter study. We measured weight, height and waist circumference, from which we then calculated BMI and waist-to-hip ratio (WHR). RESULTS: We found the CT-genotype of the SNP rs16147 to be significantly associated with lower WHRs and higher serum leptin levels in women, compared to homozygote gene carriers. No association between rs16147, WHR and serum leptin levels was found in men. CONCLUSION: Our results provide evidence that the functionally relevant SNP in the NP-Y promoter gene affects body fat distribution and serum leptin levels in women, pointing towards possible behavioral effects of NPY in obesity.

Initial response to the COVID-19 pandemic on real-life well-being, social contact and roaming behavior in patients with schizophrenia, major depression and healthy controls: A longitudinal ecological momentary assessment study.

The COVID-19 pandemic strongly impacted people's daily lives. However, it remains unknown how the pandemic situation affects daily-life experiences of individuals with preexisting severe mental illnesses (SMI). In this real-life longitudinal study, the acute onset of the COVID-19 pandemic in Germany did not cause the already low everyday well-being of patients with schizophrenia (SZ) or major depression (MDD) to decrease further. On the contrary, healthy participants' well-being, anxiety, social isolation, and mobility worsened, especially in healthy individuals at risk for mental disorder, but remained above the levels seen in patients. Despite being stressful for healthy individuals at risk for mental disorder, the COVID-19 pandemic had little additional influence on daily-life well-being in psychiatric patients with SMI. This highlights the need for preventive action and targeted support of this vulnerable population.

Psychomotor slowing in schizophrenia is associated with cortical thinning of primary motor cortex: A three cohort structural magnetic resonance imaging study.

Psychomotor slowing (PS) is characterized by slowed movements and lower activity levels. PS is frequently observed in schizophrenia (SZ) and distressing because it impairs performance of everyday tasks and social activities. Studying brain topography contributing to PS in SZ can help to understand the underlying neurobiological mechanisms as well as help to develop more effective treatments that specifically target affected brain areas. Here, we conducted structural magnetic resonance imaging (sMRI) of three independent cohorts of right-handed SZ patients (SZ#1: n = 72, SZ#2: n = 37, SZ#3: n = 25) and age, gender and education matched healthy controls (HC) (HC#1: n = 40, HC#2: n = 37, HC#3: n = 38). PS severity in the three SZ cohorts was determined using the Positive and Negative Syndrome Scale (PANSS) item #G7 (motor retardation) and Trail-Making-Test B (TMT-B). FreeSurfer v7.2 was used for automated parcellation and segmentation of cortical and subcortical regions. SZ#1 patients showed reduced cortical thickness in right precentral gyrus (M1; p = 0.04; Benjamini-Hochberg [BH] corr.). In SZ#1, cortical thinning in right M1 was associated with PANSS item #G7 (p = 0.04; BH corr.) and TMT-B performance (p = 0.002; BH corr.). In SZ#1, we found a significant correlation between PANSS item #G7 and TMT-B (p = 0.005, ρ=0.326). In conclusion, PANSS G#7 and TMT-B might have a surrogate value for predicting PS in SZ. Cortical thinning of M1 rather than alterations of subcortical structures may point towards cortical pathomechanism underlying PS in SZ.

Validating incentive salience with functional magnetic resonance imaging: association between mesolimbic cue reactivity and attentional bias in alcohol-dependent patients.

Alcohol-associated cues are able to elicit brain activations in mesocorticolimbic networks that are related to the rewarding properties of the drug. Some authors hypothesize that the activation of the mesocorticolimbic reward system triggers an attention allocation to alcohol-associated cues. Yet, no functional magnetic resonance imaging (fMRI) studies examining this proposition are available. In this fMRI study we investigate the association between attentional bias and neural cue reactivity. Thirty-eight recently abstinent alcohol-dependent patients were examined. fMRI was used to study cue reactivity during the presentation of alcohol-related pictures. A modified visual dot-probe task was used to assess attentional bias. Alcohol-dependent patients showed an attentional bias to alcohol-associated cues as well as cue-induced fMRI activation in response to alcohol-related stimuli in limbic and reward-related brain regions and visual areas. We found a positive correlation between cue-induced brain activation and attentional bias score in a network including frontal, temporal and subcortical regions. This study is the first demonstrating that, in line with previous suggestions, cue induced activation of the mesocorticolimbic reward system triggers focusing attention to substance-associated cues. However, this association could also be bidirectional with the attentional bias enhancing cue-induced neural activity.

Genetic variation in the neuropeptide Y gene promoter is associated with increased risk of tobacco smoking.

BACKGROUND: Neuropeptide Y (NPY) is a strong candidate gene regarding the pathophysiology of tobacco dependence. It has been associated with various addictive and psychiatric disorders, and closely interacts with the brain reward system. The aim of the present study was to test for association between a functional genetic variant in the NP-Y promoter gene (SNP rs16147) and tobacco smoking. METHODS: In a population-based case-control multicenter study designed for tobacco addiction research, a total of 550 Caucasian current smokers, and 544 never-smokers were genotyped for SNP rs16147 and behaviorally characterized with the State-Trait Anxiety Inventory (STAI). RESULTS: Subjects with TT genotype of the SNP rs16147 were significantly more frequently smokers than never-smokers (p = 0.046). In addition, TT genotype exhibited increased state anxiety scores compared to carriers of the C allele (p = 0.037). CONCLUSIONS: Our results provide evidence for an involvement of the functionally relevant SNP rs16147 in the pathophysiology of tobacco dependence. Further studies are needed to confirm our findings.

Involvement of orexin in the regulation of stress, depression and reward in alcohol dependence.

There is growing evidence from preclinical studies for an involvement of orexins (ORX) in the regulation of stress, affectivity and addictive behavior. The aim of our study was to gather corresponding clinical data and to elucidate the relationships between alcohol withdrawal stress, ORX plasma concentration and psychopathology. A consecutive sample of thirty-four alcohol-dependent inpatients was included in the study. Blood was drawn at onset of withdrawal and following 2 weeks of controlled abstinence in order to assess ORX, ACTH and cortisol plasma concentrations. In parallel, we assessed clinically relevant psychological distress symptoms applying the Brief Symptom Inventory (BSI). We found a significant positive correlation between ORX and global distress indices of the BSI (p ≤ 0.05). In a regression model, ORX concentration during acute withdrawal explained 24% of the variance of symptom severity (p<0.01). No association with craving, ACTH or cortisol plasma concentration was detected. Our results suggest an involvement of ORX in the affective dysregulation seen commonly in alcohol dependent patients during alcohol withdrawal. Moreover, the effects on global distress indices as well as the earlier studied effects on reinstatement of drug seeking behaviors may point on an involvement of ORX in impaired brain stress systems.

Psychological and hormonal features of smokers at risk to gain weight after smoking cessation--results of a multicenter study.

Preclinical and clinical data suggest modulating effects of appetite-regulating hormones and stress perception on food intake. Nicotine intake also interferes with regulation of body weight. Especially following smoking cessation gaining weight is a common but only partially understood consequence. The aim of this study was to examine the interaction between smoking habits, the appetite regulating hormone leptin, negative affectivity, and stress vulnerability on eating behavior in a clinical case-control study under standardized conditions. In a large population-based study sample, we compared leptin and cortisol plasma concentrations (radioimmunoassay) between current tobacco smokers with high cognitive restraint and disinhibition in eating behavior and smokers scoring low in both categories as assessed with the Three Factor Eating Questionnaire (TFEQ; Stunkard & Messick, 1985). As a measure for smoking effects on the stress axis, the saliva cortisol concentrations were compared before and after nicotine smoking. Additionally, stress perception was assessed with the Perceived Stress Scale (PSS), symptoms of depression and anxiety with the Beck Depression Inventory (BDI) and the State Trait Anxiety Inventory (STAI). In smokers showing high cognitive restraint and disinhibition we found significantly higher leptin concentrations than in the group of smokers scoring low in both categories. Furthermore there was a significant group difference in saliva cortisol concentrations after nicotine intake. Smokers showing high cognitive restraint and disinhibition were also characterized by significantly higher scores in the STAI, the PSS and the BDI. Our results suggest that smokers with a pathological eating behavior show an impaired neuroendocrine regulation of appetite and are prone to experience higher levels of stress and negative affectivity. This interaction of behavioral and neuroendocrinological factors may constitute a high risk condition for gaining weight following smoking cessation.

The German multi-centre study on smoking-related behavior-description of a population-based case-control study.

Tobacco smoking is a major risk factor for most of the diseases leading in mortality. Nicotine dependence (ND), which sustains regular smoking, is now acknowledged to be under substantial genetic control with some environmental contribution. At present, however, genetic studies on ND are mostly conducted in populations that have been poorly characterized with regard to ND-related phenotypes for the simple reason that the respective populations were not primarily collected to study ND. The German multi-centre study 'Genetics of Nicotine Dependence and Neurobiological Phenotypes', which is funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) as part of the Priority Program (Schwerpunktprogramm) SPP1226: 'Nicotine-Molecular and Physiological Effects in CNS', was intended to overcome some of these inherent problems of current genetic studies of ND. The multi-centre study is a population-based case-control study of smokers and never-smokers (n = 2396). The study was unique worldwide because it was the first large-scale genetic study specifically addressing ND with the collection of a wide range of environmental, psychosocial and neurobiological phenotypes. Study design and major population characteristics with emphasis on risk prediction of smoking status were presented in this paper.

Attention shift towards smoking cues relates to severity of dependence, smoking behavior and breath carbon monoxide.

The aim of this study was to assess the severity of dependence as a factor affecting the attentional bias of smokers towards smoking-related stimuli and to clarify contradictory results of previous studies. A visual dot probe task was administered to 51 smokers and 41 nonsmokers to assess the attentional bias. Smokers were classified into a group of less severely dependent and a group of more severely dependent smokers according to the Fagerström Test for Nicotine Dependence, the number of cigarettes smoked per day or the CO concentration in the expired air. Nicotine craving was assessed as well. The more severely dependent smokers displayed an attentional bias towards smoking-related stimuli, while smokers with less severe nicotine dependence showed a negative attentional bias which was also observed in nonsmokers. A multiple linear regression indicated that CO concentration was the only significant predictor of attentional bias. In the total group of smokers we found a positive association between attentional bias and craving for the rewarding effects of nicotine. Future studies are warranted to further enhance our understanding of factors that affect attentional bias as appetitive responses towards smoking-related stimuli might be an important target for therapeutic interventions.

Augmented stress-induced alcohol drinking and withdrawal in mice lacking functional natriuretic peptide-A receptors.

AIMS: Preclinical and clinical data suggest an involvement of atrial natriuretic peptides (ANP) in alcohol-associated psychopathology. We now present first data on alcohol drinking behaviour in mice lacking a functional natriuretic peptide-A (NPR-A) receptor. METHODS: NPR-A(-/-) and wild-type mice were given a free choice between water and increasing concentrations of alcohol (2-16%). A forced swim stress was performed thereafter on three consecutive days to investigate stress-induced alcohol drinking. Additionally, neurobehavioural alcohol withdrawal response was investigated following 14 days of forced-alcohol intake. RESULTS: Whereas basal alcohol intake did not differ between NPR-A mutants and wild-type littermates, NPR-A mutants showed an increased stress-induced alcohol intake and aggravated neurobehavioural symptoms of alcohol withdrawal. CONCLUSIONS: Mice lacking a functional NPR-A receptor represent a useful model to study the role of the ANP system in alcohol-associated pathology. To study the role of the natriuretic NPR-A gene for the modulation of risk of alcohol-related disorders, NPR-A-related polymorphisms should be targeted in clinical studies.

Learning and memory in the aetiopathogenesis of addiction: future implications for therapy?

Addiction is a chronic relapsing disorder. Even after long periods of abstinence from drugs, the risk of relapse, often precipitated by drug-associated cues, remains high. Especially learning processes have been shown to play a major role in the maintenance of addictive behaviour. Humans and animals rapidly learn cues and contexts that predict the availability of addictive drugs. Once learned, these cues and contexts initiate drug seeking, craving and relapse in both animal models and clinical studies. These observations have converged on the hypothesis that addiction represents the pathological usurpation of neural processes that normally serve reward-related learning. In this context, a substantial body of evidence suggests that several types of neuroadaptation occur, including synapse-specific adaptations of the type thought to underlie specific long-term associative memory. Consequently, understanding learning and memory processes in the brain in addiction is an important key for understanding the persistence of addiction, and it is reasonable to hypothesize that the disruption of drug-related memories may help to prevent relapses.

Avoidance of alcohol-related stimuli increases during the early stage of abstinence in alcohol-dependent patients.

AIMS: The aim of this study was to analyse initial orienting processes as well as maintenance of attention towards alcohol cues in recently detoxified alcoholics and light social drinkers. Furthermore, we investigated the influence of pre-treatment alcohol consumption and abstinence duration onto alcohol-related attentional bias. METHODS: We used an alcohol-visual-dot-probe-task with two different stimulus onset asynchronies (SOA) to examine processes of initial orienting and maintenance of attention separately (50 and 500 ms SOA). RESULTS: With short SOA, we found a positive attentional bias towards alcohol cues in alcohol-dependent patients and light social drinkers that was positively associated with pre-treatment alcohol consumption in alcoholics. Using a longer SOA, a negative attentional bias was found in light social drinkers and in patients abstinent for more than 2 weeks indicating alcohol stimuli avoidance. In patients, we found a negative correlation between attentional bias and duration of abstinence. CONCLUSIONS: After initial visual orienting towards alcohol-related stimuli, light social drinkers as well as longer abstinent alcohol-dependent patients disengage their attention. In patients, this disengagement increased during the first 3 weeks after detoxification indicating assimilation to the attentional bias pattern of light social drinkers.

Attentional bias in alcohol-dependent patients: the role of chronicity and executive functioning.

It has been suggested that the attention towards alcohol-related stimuli increases with the duration of drinking and alcohol dependence. The present study aimed to assess whether an attentional bias was present in detoxified alcohol-dependent patients, and if the magnitude of the attentional bias depended on the subject's drinking history and variables of executive functioning. Attentional bias was assessed in 30 alcohol-dependent patients using a visual dot-probe task with a picture presentation time of 50 ms. In addition, patients completed a variety of different cognitive tasks such as attention, continuous performance, working memory, set shifting and inhibitory control tests. Based on correlation analysis we split the patient sample on the median with regard to the duration of alcohol dependence and our results indicated a significant attentional bias towards alcohol-associated pictures in patients dependent for less than 9 years, but not in patients with a longer duration of dependence. The two patient samples differed significantly with regard to attention and working memory functioning with patients who were dependent for more than 9 years showing a greater impairment. When impairment of attention and working memory were controlled for, the group differences in attentional bias were no longer significant. Our results indicate that differences with regard to drinking-related variables as well as cognitive functioning seem to modulate attentional bias and need to be taken into account in models of drinking maintenance.

Nalmefene Reduces Reward Anticipation in Alcohol Dependence: An Experimental Functional Magnetic Resonance Imaging Study.

BACKGROUND: Nalmefene is a µ and δ opioid receptor antagonist, κ opioid receptor partial agonist that has recently been approved in Europe for treating alcohol dependence. It offers a treatment approach for alcohol-dependent individuals with "high-risk drinking levels" to reduce their alcohol consumption. However, the neurobiological mechanism underpinning its effects on alcohol consumption remains to be determined. Using a randomized, double-blind, placebo-controlled, within-subject crossover design we aimed to determine the effect of a single dose of nalmefene on striatal blood oxygen level-dependent (BOLD) signal change during anticipation of monetary reward using the monetary incentive delay task following alcohol challenge. METHODS: Twenty-two currently heavy-drinking, non-treatment-seeking alcohol-dependent males were recruited. The effect of single dose nalmefene (18 mg) on changes in a priori defined striatal region of interest BOLD signal change during reward anticipation compared with placebo was investigated using functional magnetic resonance imaging. Both conditions were performed under intravenous alcohol administration (6% vol/vol infusion to achieve a target level of 80 mg/dL). RESULTS: Datasets from 18 participants were available and showed that in the presence of the alcohol infusion, nalmefene significantly reduced the BOLD response in the striatal region of interest compared with placebo. Nalmefene did not alter brain perfusion. CONCLUSIONS: Nalmefene blunts BOLD response in the mesolimbic system during anticipation of monetary reward and an alcohol infusion. This is consistent with nalmefene's actions on opioid receptors, which modulate the mesolimbic dopaminergic system, and provides a neurobiological basis for its efficacy.

Effects of D-cycloserine on extinction of mesolimbic cue reactivity in alcoholism: a randomized placebo-controlled trial.

RATIONALE: Mesocorticolimbic reactivity to alcohol-associated cues has been shown to be associated with relapse to renewed drinking and to be decreased by cue-exposure-based extinction training (CET). Evidence from preclinical studies suggests that the extinction of conditioned alcohol-seeking behavior might be facilitated by drugs increasing N-methyl-D-aspartate (NMDA) receptor-associated memory consolidation. OBJECTIVES: In this study, we assessed the efficacy of CET treatment supplemented with the partial NMDA-receptor agonist D-cycloserine (DCS) at reducing mesolimbic cue reactivity (CR), craving, and relapse risk in alcoholism. METHODS: In a randomized, placebo-controlled, double-blind study, we recruited 76 recently detoxified abstinent alcohol-dependent patients. Thirty-two (16 DCS, 16 placebo) patients showed cue-induced ventral-striatal activation measured with functional magnetic resonance imaging (fMRI) prior to treatment and were thus included in the efficacy analyses. After inpatient detoxification, patients underwent nine sessions of CET spaced over 3 weeks, receiving either 50 mg DCS or placebo 1 h prior to each CET session. FMRI was conducted before treatment and 3 weeks after treatment onset. RESULTS: Following treatment with CET plus DCS, cue-induced brain activation in the ventral and dorsal striatum was decreased compared to treatment with CET plus placebo. Elevated posttreatment ventral striatal CR and increased craving (assessed using the Obsessive Compulsive Drinking Scale) were associated with increased relapse risk. CONCLUSIONS: DCS was shown to augment the effect of CET for alcohol-dependent subjects. The interaction between craving and ventral-striatal CR on treatment outcome suggests that CET might be especially effective in patients exhibiting both high craving and elevated CR.

The association of the appetitive peptide acetylated ghrelin with alcohol craving in early abstinent alcohol dependent individuals.

OBJECTIVE: Recent preclinical and clinical studies suggested ghrelin to have an orexigenic role in regulating appetite and energy balance. Preclinical studies also provided support for an important role of ghrelin in the neurobiology of addiction-related reward pathways, affecting the self-administration of alcohol and drugs as well as conditioned place preference. In contrast, clinical data have until now failed to support an association between ghrelin and alcohol craving, possibly due to the fact that these studies have analyzed the pharmacologically inactive, preprohormone ghrelin instead of ghrelin in its active, acetylated form. MATERIALS AND METHODS: Our study sample was a group of 61 alcohol-dependent male inpatients. We assessed their plasma concentrations of both active and total ghrelin, using blood samples taken twice during the study: once at the onset of withdrawal, 12-24h after admission, and then again after 14 days of controlled abstinence. During this time, we also assessed the patients' alcohol cravings (applying the obsessive compulsive drinking scale, or OCDS), symptoms of depression (Beck Depression Inventory; BDI) and anxiety (State Trait Anxiety Inventory; STAI). The severity of alcohol dependence was assessed using the alcohol dependence scale (ADS). RESULTS: We found a significant positive correlation between the plasma concentration of active ghrelin and alcohol craving in both blood samples. Plasma concentrations of active ghrelin increased significantly during early abstinence. In a linear regression model, the plasma concentration of active ghrelin on day one, the scores of the ADS, and the BDI explained 36% of the variance in OCDS sum score (p<0.0001). By day 14, these same factors accounted for 54% (p<0.0001). We did not detect any association between the plasma concentration of total ghrelin and patients' alcohol cravings. CONCLUSION: Our results suggest that biologically active, acetylated ghrelin is involved in reward-associated craving during alcohol withdrawal and early abstinence in alcohol-dependent patients. Antagonizing ghrelin at its central growth-hormone secretagogue receptors (GHS-R1A) in the ventral tegmental area (VTA) may prove to be a novel pharmacological target in a future treatment for craving and relapse in alcoholics.

Association of leptin with food cue-induced activation in human reward pathways.

CONTEXT: Overlapping neurobiological pathways between obesity and addiction disorders are currently in discussion. Whereas the hypothalamic regulation of energy homeostasis by endocrine feedback signals has been widely investigated, its interplay with mesolimbic reward-associated pathways represents a rich field of future research. OBJECTIVE: To assess changes in regional brain activation in response to food-related cues in association with body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and the plasma concentration of the appetite-regulating peptide leptin. DESIGN: Case-control study. SETTING: Academic addiction and brain imaging center, Central Institute of Mental Health, Mannheim, Germany. PARTICIPANTS: Twenty-one obese subjects (BMI >30) and 23 age- and sex-matched nonobese control subjects (BMI 18.5-24.0) recruited by advertisements. MAIN OUTCOME MEASURES: Regional brain activation (blood oxygen level-dependent response) in response to visual cue presentation and association of the brain activation with BMI and plasma leptin concentration. RESULTS: Significant positive relationships were observed for food cue-induced brain activations in the ventral striatum in association with the plasma concentration of leptin (r = 0.27; P = .04) and with BMI (r = 0.47; P = .001). CONCLUSIONS: Data suggest a physiological role of satiety factors in modulating the responsivity of mesolimbic circuits to food cues. Moreover, an altered homeostatic feedback regulation of reward pathways might explain addictionlike behavior and the inability of obese patients to adapt food intake to physiological needs.