Anne Koopmann

Orexin and leptin are associated with nicotine craving: A link between smoking, appetite and reward

OBJECTIVE Preclinical data suggest modulating effects of both orexin/hypocretin and leptin on dopaminergic transmission in mesolimbic reward pathways. This indicates a possible role of both peptides in reward function and motivation, and thus in addictive diseases. The aim of this study was to examine the possible association between orexin and leptin, and nicotine craving in smokers in a clinical case-control study under standardized conditions. METHODS We compared orexin and leptin, ACTH and cortisol plasma concentrations (RIA) between tobacco smokers (n=60) during early nicotine withdrawal and healthy controls (n=64). Motivational aspects of nicotine craving were additionally assessed in the smoking participants using the Questionnaire of Smoking Urges (QSU). RESULTS As main results we detected a significant negative correlation between orexin plasma concentration and nicotine craving (r=-0.28; p<.05), and a positive association between craving and leptin plasma concentration (r=0.29; p<.05). CONCLUSIONS Our results show an association between craving for nicotine and plasma concentrations of orexin and leptin suggesting that both peptides interfere with the dopaminergic transmission during nicotine withdrawal in a bidirectional manner and, thus, modulate craving for nicotine.

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.

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.

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.

Neurobiological correlates of physical self-concept and self-identification with avatars in addicted players of Massively Multiplayer Online Role-Playing Games (MMORPGs)

AIMS MMORPG addiction has been associated with self-concept impairments and increased identification with the own avatar. Yet, the underlying neurobiological mechanisms of self-identification with avatars, especially reflected in the left angular gyrus (AG), have only been assessed in regular gamers. Therefore, the study aims to examine neurobiological processes in addicted MMORPG players while evaluating their own and their personal avatars body image (physical self-concept). METHODS Sixteen addicted and seventeen non-addicted gamers underwent functional Magnetic Resonance Imaging (fMRI) while viewing images of themselves, their own avatar and unfamiliar persons. The Body Image Questionnaire (FKB-20) and Visual Analog Scales (VAS) assessing the degree of attractiveness, sympathy and gender identity of the self, of the avatar as well as of the unfamiliar persons were applied. RESULTS Addicts showed a significantly extended negative body image and lower gender identity levels as well as decreased bilateral brain activations in the AG and the middle occipital gyrus during self-perception. They further exhibited higher activations in the left AG during avatar-perception. Regression analyses in the overall group and in addicted gamers indicated a significant positive correlation between gender identity and brain activation in the left AG during self-perception. CONCLUSIONS Our results confirm addicted MMORPG players to have physical self-concept deficits which may be related to hypoactivations in the AG. The findings further indicate addicted gamers to have a tendency to identify themselves easier with their own avatar than with their real self. Lower gender identity levels might be associated with physical self-concept deficits in MMORPG addiction.

Effects of Cigarette Smoking on Plasma Concentration of the Appetite-Regulating Peptide Ghrelin

Background: Weight gain is a common but only a partially understood consequence of smoking cessation. Existing data suggest modulating effects of the orexigenic peptide ghrelin on food intake. The aim of the present study was to investigate the effect of tobacco withdrawal on plasma concentration of acetylated and total ghrelin. Methods: Fifty four normal-weighted smokers and 30 non-smoking healthy controls were enrolled in our study. Concentrations of acetylated and total ghrelin were measured in blood plasma drawn two hours after a standardized meal and three hours after the smokers smoked their last cigarette. The severity of tobacco addiction was assessed based on cotinine plasma concentration, the Fagerström Test for Nicotine Dependence (FTND) and the number of cigarettes smoked per day. Results: The plasma concentration of acetylated ghrelin, but not total ghrelin, was significantly higher in smokers than in non-smokers. Moreover, we found significant negative correlations between acetylated ghrelin and all measures of the severity of nicotine dependence. Conclusions: Early abstinence from tobacco smoking seems to be associated with increased plasma concentration of the orexigenic peptide acetylated ghrelin. This could be one reason for increased food craving during nicotine withdrawal and subsequent weight gain. Smokers might compensate these effects by increasing tobacco intake.

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.

Propofol Addiction Initiated by Anesthetic Use

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Supervised disulfiram in relapse prevention in alcohol-dependent patients suffering from comorbid borderline personality disorder--a case series.

AIMS Disulfiram is widely used to prevent alcoholic relapse. However, due to the intended adverse reaction with ethanol, some believe that its use is dangerous for patients with personality disorders or psychiatric comorbidities because of their increased risk of impulsivity or suicidal behaviour. We examined the safety and efficacy in relapse prevention of a series of alcoholics with borderline personality disorder (BPD). METHODS Case history study of patients diagnosed with BPD, prescribed disulfiram in a dose of 1.5-2.5 g/week, supervised by a physician in up to three brief contacts per week. RESULTS Two out of eight patients remained completely abstinent during the supervised disulfiram therapy over a mean period of 9.25 months. Adherence to treatment was 18.44 +/- 21.78 months. The first relapse occurred after 1.38 +/- 1.41 months. The cumulated time of abstinence was 16.88 +/- 20.48 months. The overall tolerability was considered to be high; dizziness and fatigue appeared in all patients at the beginning of the therapy but did not persist. No serious adverse events or ethanol-disulfiram interactions were observed. No suicidal behaviour was reported. CONCLUSIONS Although case observations should be interpreted with caution, supervised disulfiram seems to deserve further investigation in patients with comorbid BPD, for whom it appears to help prevent alcoholic relapse.

Oxytocin Reduces Alcohol Cue-Reactivity in Alcohol-Dependent Rats and Humans

Approved pharmacological treatments for alcohol use disorder are limited in their effectiveness, and new drugs that can easily be translated into the clinic are warranted. One of those candidates is oxytocin because of its interaction with several alcohol-induced effects. Alcohol-dependent rats as well as post-mortem brains of human alcoholics and controls were analyzed for the expression of the oxytocin system by qRT-PCR, in situ hybridization, receptor autoradiography ([125I]OVTA binding), and immunohistochemistry. Alcohol self-administration and cue-induced reinstatement behavior was measured after intracerebroventricular injection of 10 nM oxytocin in dependent rats. Here we show a pronounced upregulation of oxytocin receptors in brain tissues of alcohol-dependent rats and deceased alcoholics, primarily in frontal and striatal areas. This upregulation stems most likely from reduced oxytocin expression in hypothalamic nuclei. Pharmacological validation showed that oxytocin reduced cue-induced reinstatement response in dependent rats—an effect that was not observed in non-dependent rats. Finally, a clinical pilot study (German clinical trial number DRKS00009253) using functional magnetic resonance imaging in heavy social male drinkers showed that intranasal oxytocin (24 IU) decreased neural cue-reactivity in brain networks similar to those detected in dependent rats and humans with increased oxytocin receptor expression. These studies suggest that oxytocin might be used as an anticraving medication and thus may positively affect treatment outcomes in alcoholics.