Jochen Mutschler

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.

Pronounced paranoia as a result of cocaine-disulfiram interaction: case report and mode of action.

To the Editors: Restless legs syndrome (RLS) is a common neurological disorder characterized by dysesthetic sensations in the legs and irresistible urge to move them. Arm restlessness has been reported as an accompanying feature in up to 48.7% of patients with RLS, although involvement of upper limbs is rarely reported as an initial symptom of RLS. The term restless arms syndrome (RAS) has been proposed for the restlessness of the arms with clinical features similar to RLS. Drug-induced RLS has been described under treatment with various drugs, including the atypical antipsychotics olanzapine, risperidone, quetiapine, and clozapine. However, to the best of our knowledge, there are as yet no reports on drug-induced RAS without RLS. Only 1 case of neuroleptic-induced restlessness of the arms has been reported, however, in the context of akathisia. In the following, we report on such a case whereby RAS developed under treatment with olanzapine.

Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence

Background Cocaine use continues to be a public health problem, yet there is no proven effective pharmacotherapy for cocaine dependence. A promising approach to treating cocaine dependence may be agonist-replacement therapy, which is already used effectively in the treatment of opioid and tobacco dependence. The replacement approach for cocaine dependence posits that administration of a long-acting stimulant medication should normalize the neurochemical and behavioral perturbations resulting from chronic cocaine use. One potential medication to be substituted for cocaine is methylphenidate (MPH), as this stimulant possesses pharmacobehavioral properties similar to those of cocaine. Aim To provide a qualitative review addressing the rationale for the use of MPH as a cocaine substitute and its clinical potential in the treatment of cocaine dependence. Methods We searched MEDLINE for clinical studies using MPH in patients with cocaine abuse/dependence and screened the bibliographies of the articles found for pertinent literature. Results MPH, like cocaine, increases synaptic dopamine by inhibiting dopamine reuptake. The discriminative properties, reinforcing potential, and subjective effects of MPH and cocaine are almost identical and, importantly, MPH has been found to substitute for cocaine in animals and human volunteers under laboratory conditions. When taken orally in therapeutic doses, its abuse liability, however, appears low, which is especially true for extended-release MPH preparations. Though there are promising data in the literature, mainly from case reports and open-label studies, the results of randomized controlled trials have been disappointing so far and do not corroborate the use of MPH as a substitute for cocaine dependence in patients without attention deficit hyperactivity disorder. Conclusion Clinical studies evaluating MPH substitution for cocaine dependence have provided inconsistent findings. However, the negative findings may be explained by specific study characteristics, among them dosing, duration of treatment, or sample size. This needs to be considered when discussing the potential of MPH as replacement therapy for cocaine dependence. Finally, based on the results, we suggest possible directions for future research.

Dextromethorphan Withdrawal and Dependence Syndrome

BACKGROUND The N-methyl-D-aspartate (NMDA) antagonist dextromethorphan has been available in pharmacies without a prescription since 1954 as an antitussive agent. There is an alarming increase in reports of its abuse. Dextromethorphan is avidly taken, mainly by young people, as a psychoactive drug. The currently available data yield incomplete information about the extent of the problem and its significance for addiction medicine in Germany. CASE PRESENTATION AND COURSE We report the case of a 44-year-old man who became dependent on dextromethorphan through years of abuse, buying the substance for himself without a prescription in German pharmacies. He told us he had taken it regularly for six years. He had become dependent on dextromethorphan, ultimately taking it in a dose of 1800 mg daily. This led him to overt neglect of his work and leisure activities. A urine sample taken on admission to the hospital was found to contain dextromethorphan. During inpatient detoxification, he developed an vegetative withdrawal syndrome consisting of craving, diaphoresis, nausea, hypertension, and tachycardia. He was treated on our ward for three weeks, and a stay in a residential detoxification facility was planned thereafter. CONCLUSION Dextromethorphan is a psychotropic substance that carries a potential for abuse and dependence. On the basis of the currently available data, its reclassification as a prescription drug should be considered.

Functional Social Support within a Medical Supervised Outpatient Treatment Program

Background: This study examined functional social support (FSS) and its impact on treatment outcome in alcohol-dependent outpatients treated with supervised disulfiram. Method: FSS was assessed cross-sectionally in 46 severe alcohol-dependent patients participating in a close-meshed biopsychosocial treatment program. The FSS was measured with the Medical Outcome Study Social Support Survey. Results: We found significantly higher FSS levels in patients with a current partnership. No significant influence was found of the FSS on days until relapse and retention time. However, FSS was positively correlated with cumulative abstinence. In comparison with another patient sample, it can be shown that the patients of the close-meshed biopsychosocial treatment program seemed to perceive more FSS, presumably through the higher frequency of the outpatient treatment contacts. Conclusion: High FSS is associated with a current partnership and with a higher cumulative time of abstinence through close professional supervision. A better understanding of the underlying mechanisms of social relationships in alcohol-dependent patients would probably help to improve treatment outcome in the future.

Disulfiram, an Option for the Treatment of Pathological Gambling?

AIM Pathological gambling and comorbid alcohol dependence often occur in combination. Disulfiram is one of the proven drugs for alcohol dependence. In addition to its inhibiting acetaldehyde dehydrogenase, disulfiram inhibits dopamine beta-hydroxylase and may thereby increase dopamine and decrease norepinephrine cerebral concentrations. Because there may be common neurochemical substrates and neuronal circuits for pathological gambling and addiction, we wished to explore the effect of disulfiram in gambling. METHOD We describe the outcome of a patient with alcohol dependence and pathological gambling treated with disulfiram D. RESULTS During treatment with disulfiram, the patient reported that his desire to gamble disappeared entirely. Follow-up indicated that he has not gambled for >12 months. CONCLUSIONS Although uncontrolled case observations should be interpreted with caution, disulfiram deserves further investigation in pathological gambling.

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.

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.

Rivastigmine Reduces Tobacco Craving in Alcohol-dependent Smokers

INTRODUCTION Although alcohol-dependent smokers represent an important group for applying smoking interventions, a sufficient pharmacotherapy has not been established in this high-risk group so far. METHODS In order to examine the effect of the acetylcholinesterase inhibitor rivastigmine on tobacco dependence, we performed a 12-week, randomized, placebo-controlled trial. 26 alcohol-dependent smokers were randomized to rivastigmine 6 mg/day (n=14) or placebo (n=12). Assessments on addictive behavior included carbon monoxide (CO), severity of tobacco dependence (FTND), daily smoked cigarettes (diaries), and craving for tobacco (QSU) and alcohol (AUQ). RESULTS ANOVA revealed a significant treatment-by-time interaction for tobacco consumption and tobacco craving (each p<0.0001). The rivastigmine group showed a decrease in daily smoked cigarettes (-30%), in exhaled carbon monoxide (-32%) and in tobacco craving (-18%) whereas controls did not show significant changes. ANCOVA revealed rivastigmine effects to be more prominent in smokers suffering from more severe tobacco dependence. None of the patients developed an alcohol relapse or an increase in alcohol craving. DISCUSSION Our preliminary data indicate an effect of rivastigmine on tobacco craving and consumption. This pilot study encourages further investigation of acetylcholinesterase-inhibitors as a promising treatment approach regarding tobacco dependence.

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.