C. von der Goltz

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.

Bedeutung von Lernen und Gedächtnis in der Pathogenese von Suchterkrankungen

The persistance of addiction-associated cognitions and behavior is caused, in least part, by long-lasting drug-associated memories. Relapses, triggered by exposure to drug-associated cues, contribute considerably to the maintenance of addiction and are, even after drug-free periods for years, a major challenge in the treatment of addiction. An important advance in understanding the underlying pathophysiology derives from recent research results showing similarities between the process of drug addiction and physiological neural plasticity in learning and memory. In the focus of attention are basic mechanisms involving dopamine, glutamate, and their cellular and molecular targets leading to drug-induced synaptic alterations in the mesolimbic reward system. There is growing evidence from preclinical and clinical studies that specific treatments such as extinction training and cue-exposure therapy are effective. The challenge of future research is to determine which drug-induced adaptations are relevant to the pathophysiology of addiction and to generate more efficient therapies for extinction of addiction-associated cognitions and behavior.

Intraperitoneal Atrial Natriuretic Peptide Attenuates Anxiety-related Behaviour during Alcohol Withdrawal in Mice

Converging evidence from both preclinical and clinical studies suggests atrial natriuretic peptide (ANP) as a potential target for treatment of alcohol withdrawal and dependence. Since ANP tightly interacts with hypothalamic-pituitary-adrenocortical (HPA) axis activity, especially the modulation of stress-related anxiety during alcohol withdrawal might mediate these effects. We have now evaluated the anxiolytic activity of intraperitoneal ANP application during alcohol withdrawal in alcohol-habituated mice (C57/Bl6J). Anxiety related behaviour was attenuated during ethanol withdrawal following application of ANP (60 μg/kg) vs. saline. Our results support that anxiolytic effects of ANP mediate ANP-related gene effects with clinical data on withdrawal symptomatology.

P02-330 - Food-cue evoked activation of reward pathways is modulated by the satiety factor leptin: An fMRI study in obese and normal weight subjects

Introduction Mechanisms contributing to the development and maintenance of obesity remain to be elucidated especially regarding the interaction between appetite regulating hormones and mesolimbic reward circuits. Leptin was recently suggested to attenuate dopamine release in mesolimbic reward pathways. We now test the functional relevance assessing whether leptin plasma concentration affects the BOLD-response following the presentation of food cues. Methods 21 obese and 23 normal weight subjects were investigated. Visual food cues and neutral stimuli were presented in a block design during fMRI. Blood-samples were collected immediately prior to the scan to assess plasma leptin concentration. Using linear regression analyses, the association between BOLD response to food cues and the body mass index (BMI) as well as plasma leptin concentration was examined. Results Food-cues elicited activation of large cortical and subcortical networks, whereas only in obese patients food cues activated the left ventral and right dorsal striatum. Mean plasma concentration of leptin was significantly increased in obese subjects compared to normal weight controls. We found a significant positive correlation between the food cue-induced BOLD signal change in the ventral striatum and leptin plasma concentration. Furthermore, ventral and dorsal striatum BOLD response to food cues was significantly positive associated with the body mass index (BMI). Conclusions These findings suggest a physiological role of the satiety factor leptin in modulating responsivity of reward pathways towards food cues. Altered homeostatic feedback regulation of the mesolimbic brain reward circuit might explain the inability of obese patients to adapt their food intake according to physiologically needs.

PW01-252 - Association between orexin, leptin and craving for nicotine

Although the majority of studies associated the function of orexin neurons with arousal and sleep and leptin with balancing energy expenditure and food craving these neuropeptides were also shown to directly affect dopaminergic transmission in mesolimbic reward pathways. This indicates a possible role for orexin and leptin in reward function and motivation and thus in addictive diseases. Aim of our study was to test whether both peptides are involved in nicotine craving in a standardized setting. We studied orexin and leptin plasma concentrations (RIA) in tobacco smokers (n = 60) compared to healthy controls (n = 64). In smoking subjects we assessed craving for nicotine applying the Questionnaire of Smoking Urges (QSU) after three hours of withdrawal from nicotine. As main results we found a significant negative correlation between orexin plasma concentration and nicotine craving (r = -0.28; p

S64-03 Pharmacological disruption of alcohol-related memories - therapeutic impact of the theory of memory reconsolidation

Long-lasting memories that associate environmental stimuli with the effects of alcohol are known to be a main cause of relapse and are a major challenge in the treatment of alcohol addiction. It is reasonable to hypothesize that disrupting consolidated alcohol-related memories might help to prevent relapses. The reconsolidation theory states that a consolidated memory could again become labile and susceptible to disruption by protein synthesis inhibition or NMDA-antagonism after memory retrieval. This has been shown for cocaine- and morphine-associated memories in several recent studies. The aim of our investigations was to examine in an animal model for cue-induced relapse to alcohol-seeking behavior whether the behavioral impact of previously conditioned alcohol associated cues is significantly reduced by blocking the reconsolidation of learned alcohol associations. We show that reconsolidation of alcohol memories is disrupted by post-retrieval ICV-administration of the protein synthesis inhibitor anisomycin. Similarly, post-retrieval i.p.-administration of the NMDA antagonist MK-801 reduced alcohol seeking behavior during the following test day as compared to vehicle treated rats. Pharmacological disruption of reconsolidation of alcohol-associated memories may thus provide a potential therapeutic strategy for the prevention of relapse in alcohol addiction.

P01-84 Disrupting reconsolidation of alcohol memories reduces cue-induced alcohol seeking behavior in rats

In humans alcohol seeking behavior is frequently evoked by the retrieval of memories associated with an alcohol experience. Consolidated memories can become labile if reactivated by reexposure. The aim of our study was to examine whether the behavioral impact of previously conditioned alcohol associated cues is significantly reduced by blocking the reconsolidation of the previously learned alcohol associations that are retrieved by reexposition. For this purpose we applied an animal model for cue-induced relapse to alcohol-seeking behavior. We show that post-retrieval i.p.-administration of 0.1 mg/kg of the NMDA antagonist MK-801 (n=8-10 per group) significantly reduced alcohol seeking behavior during the following test day as compared to vehicle treated animals. Similarly, memory reconsolidation was disrupted by ICV administration of 400 μg of the protein synthesis inhibitor anisomycin (n=9-11 per group). Pharmacological disruption of reconsolidation of alcohol-associated memories may thus provide a potential therapeutic strategy for the prevention of relapse in alcohol addiction.

P01-85 Association between orexin plasma concentration and psychopathology in alcohol dependent patients during acute detoxification

Aims The orexins (hypocretins) are neuropeptides recently identified as neurotransmitters in lateral hypothalamus neurons. Although the majority of studies associated the function of orexin neurons with arousal and sleep, these neurons also project to reward-associated brain regions, including the nucleus accumbens and ventral tegmental area. This indicates a possible role for orexins in reward function and motivation and thus in addictive diseases. Additionally, there is growing evidence from preclinical studies for an involvement of orexins in the regulation of stress, affectivity and drug seeking behavior. Method We investigated orexin plasma concentrations and psychological symptoms in a sample of 34 alcohol dependent subjects on day 1 and day 14 of detoxification. For this purpose we used the Brief Symptom Inventory (BSI) as well as the Obsessive-Compulsive Drinking Scale to identify self-reported clinically relevant psychological symptoms including alcohol craving. Results As a main result a significant positive correlation between orexin plasma concentration and depression as well as global distress indicies of the BSI was detected during early withdrawal (day 1), which is not shown after detoxification on day 14. No association with subjective craving for alcohol was found. Conclusion Our data indicate that orexins may be directly involved in affective dysregulation in alcohol dependent patients; moreover the effects of orexins on reinstatement of drug seeking behaviors might be mediated by impaired brain stress systems.

Bedeutung von Lernen und Gedächtnis in der Pathogenese von Suchterkrankungen@@@Learning and memory in the pathogenesis of addiction

The persistance of addiction-associated cognitions and behavior is caused, in least part, by long-lasting drug-associated memories. Relapses, triggered by exposure to drug-associated cues, contribute considerably to the maintenance of addiction and are, even after drug-free periods for years, a major challenge in the treatment of addiction. An important advance in understanding the underlying pathophysiology derives from recent research results showing similarities between the process of drug addiction and physiological neural plasticity in learning and memory. In the focus of attention are basic mechanisms involving dopamine, glutamate, and their cellular and molecular targets leading to drug-induced synaptic alterations in the mesolimbic reward system. There is growing evidence from preclinical and clinical studies that specific treatments such as extinction training and cue-exposure therapy are effective. The challenge of future research is to determine which drug-induced adaptations are relevant to the pathophysiology of addiction and to generate more efficient therapies for extinction of addiction-associated cognitions and behavior.