Effects of cortisol administration on craving in heroin addicts.

Heroin dependence is a severe and chronically relapsing substance use disorder with limited treatment options. Stress is known to increase craving and drug-taking behavior, but it is not known whether the stress hormone cortisol mediates these stress effects or whether cortisol may rather reduce craving, for example, by interfering with addiction memory. The aim of the present study was to determine the effects of cortisol administration on craving in heroin-dependent patients and to determine whether the effects depend on the daily dose of heroin consumption. We used a double-blind, placebo-controlled, cross-over study in 29 heroin-dependent patients in a stable heroin-assisted treatment setting. A single oral dose of 20 mg of cortisol or placebo was administered 105 min before the daily heroin administration. The primary outcome measure was cortisol-induced change in craving. Secondary measures included anxiety, anger and withdrawal symptoms. For the visual analog scale for craving, we found a significant interaction (P = 0.0027) between study medication and heroin-dose group (that is, daily low, medium or high dose of heroin). Cortisol administration reduced craving in patients receiving a low dose of heroin (before heroin administration: P = 0.0019; after heroin administration: P = 0.0074), but not in patients receiving a medium or high dose of heroin. In a picture-rating task with drug-related pictures, cortisol administration did not affect the ratings for the picture-characteristic craving in all the three heroin-dose groups. Cortisol also did not significantly affect secondary outcome measures. In conclusion, a single administration of cortisol leads to reduced craving in low-dose heroin addicts. The present findings might have important clinical implications with regard to understanding stress effects and regarding treatment of addiction.

[Psychosocial Treatment of Addictive Disorders--An Overview of Psychotherapeutic Options and their Efficacy]. / Psychosoziale Behandlungen bei Suchterkrankungen--Suchtspezifische Psychotherapieformen und ihre Wirksamkeit.

Addictive disorders are chronic relapsing conditions marked by compulsive and often uncontrolled use of psychotropic substances or stimuli. In this review, we present and discuss the current specific psychosocial interventions for addictive disorders and their effectiveness. In particular cognitive behavioral therapy, motivational interviewing, relapse prevention, the community reinforcement approach, and contingency management were found to be effective. For these psychotherapeutic treatments, mostly moderate effect sizes have been found. Their effectiveness seems to be highest in cannabis dependence. Empirical evidence for dependence on "hard" drugs is largest for contingency management, while for alcohol dependence motivational interviewing and the community reinforcement approach show the largest effect sizes. Presumably, combinations of different approaches as well as online interventions will bring further progress in the psychosocial treatment of addictive disorders in the future.

Increased functional connectivity in the resting-state basal ganglia network after acute heroin substitution.

Reinforcement signals in the striatum are known to be crucial for mediating the subjective rewarding effects of acute drug intake. It is proposed that these effects may be more involved in early phases of drug addiction, whereas negative reinforcement effects may occur more in later stages of the illness. This study used resting-state functional magnetic resonance imaging to explore whether acute heroin substitution also induced positive reinforcement effects in striatal brain regions of protracted heroin-maintained patients. Using independent component analysis and a dual regression approach, we compared resting-state functional connectivity (rsFC) strengths within the basal ganglia/limbic network across a group of heroin-dependent patients receiving both an acute infusion of heroin and placebo and 20 healthy subjects who received placebo only. Subsequent correlation analyses were performed to test whether the rsFC strength under heroin exposure correlated with the subjective rewarding effect and with plasma concentrations of heroin and its main metabolites morphine. Relative to the placebo treatment in patients, heroin significantly increased rsFC of the left putamen within the basal ganglia/limbic network, the extent of which correlated positively with patients' feelings of rush and with the plasma level of morphine. Furthermore, healthy controls revealed increased rsFC of the posterior cingulate cortex/precuneus in this network relative to the placebo treatment in patients. Our results indicate that acute heroin substitution induces a subjective rewarding effect via increased striatal connectivity in heroin-dependent patients, suggesting that positive reinforcement effects in the striatum still occur after protracted maintenance therapy.

GSK3ß phosphorylation of the KLF6 tumor suppressor promotes its transactivation of p21.

KLF6, a ubiquitously expressed Krüppel-like transcription factor, is frequently inactivated in human cancer and has significant roles in cellular proliferation, apoptosis, differentiation and development. A key mechanism of KLF6-mediated growth suppression is through p53-independent transactivation of p21. Several cancer-derived KLF6 mutants lead to the loss of p21-mediated growth suppression through an unknown mechanism. Because several colorectal cancer and hepatocellular carcinoma-derived KLF6 mutations affect a glycogen synthase kinase 3ß (GSK3ß) phosphorylation consensus site, we investigated the role of GSK3ß in the regulation of KLF6 function. Based on transient transfection, GSK3ß augments the transactivation of a p21 promoter luciferase by KLF6. Reciprocal co-immunoprecipitation of hemagglutinin (HA)-GSK3ß and Flag-KLF6 validated the interaction between these two proteins. KLF6 phosphorylation is augmented in the presence of GSK3ß based on in vitro and in vivo (32)P incorporation assays. Site-directed mutagenesis of the candidate phosphorylation sites to alanines ('KLF6-4A' phosphomutant) eliminated a higher molecular weight phosphorylated isoform of KLF6 based on western blot. GSK3ß augmented the transactivation by wild-type KLF6, but not KLF6-4A, towards the p21 promoter, and increased p21 protein. Functionally, GSK3ß enhanced KLF6-mediated growth suppression, which was abrogated by the KLF6-4A phosphomutant. These data establish that GSK3ß directly phosphorylates KLF6, which augments its induction of p21 and resultant growth suppression. This interaction may account for the growth-promoting effects of cancer-derived KLF6 mutants that lack tumor suppressor activity.

Lithium-induced suicidal erythrocyte death.

Lithium (Li+), an effective drug for treatment of bipolar disorders, is known to alter several Ca²+ transporting systems. Increased cellular Ca²+ has in turn been shown to stimulate eryptosis, the suicidal death of erythrocytes. Eryptosis is characterised by exposure of phosphatidylserine (PS) at the erythrocyte surface and by cell shrinkage. The present experiments explored whether Li+ influences eryptosis. In erythrocytes from healthy volunteers, cytosolic Ca²+ activity (Fluo-3 fluorescence), cell volume (forward scatter) and PS exposure (annexin V binding) were determined by fluorescence-activated cell sorting analysis. Exposure to Li+ (≥ 1 mM) did not significantly modify forward scatter but significantly increased cytosolic Ca²+ activity (within 3 h) and annexin binding (within 48 h). The effect was paralleled by increase of cellular adenosine triphosphate concentration. Glucose depletion (24 h) strongly increased PS exposure, an effect significantly enhanced in the presence of Li+ (≥ 1 mM). In conclusion, Li+ triggers suicidal erythrocyte death, an effect at least partially due to increase of cytosolic Ca²+ activity.

[Prevalence and role of psychiatric disorders in disability]. / Prävalenz und Rolle psychiatrischer Erkrankungen bei Einschränkung der beruflichen Leistungsfähigkeit.

Common risk factors for the receipt of disability income (DI) are psychiatric diagnosis at the time of conscription, showing low personal responsibility and job satisfication, unemployment after graduation, low rating on an "IQ" test, low educational level, part-time employment, isolation, separation, smoking, problem drinking, poor subjective state of health and well-being. Psychiatric diagnoses are considered to be the main reason for disability income in women and rank third in men. With average retirement age of 39 for males and 42 for females, schizophrenia is the most important single reason for early retirement before age 40. Major depression has been shown to be the fourth leading cause of DI worldwide. Personality disorders, which display primarily antisocial, histrionic, emotionally unstable and narcissistic behaviour (Cluster B personality disorders) have been associated with an earlier age of work disability, and borderline personality has been associated with failure to return to work. A dependent, schizoid, paranoid and antisocial personality tends to be associated with an increased risk of developing disability. A subtype of adaptation disorder that is characterised primarily by lasting embitterment after exceptional life events, which violate basic beliefs, namely post-traumatic embitterment disorder, shows up highly the development of DI. However, most of the patients applying for a DI have neither been sufficiently diagnosed nor received adequate psychiatric and/or psychotherapeutic treatment when they claim on their DI policy. Thus, the prognosis of the diseases listed above could well be improved at least for some patients depending on their disease (10-80 %).

Serotonergic effects of smoking are independent from the human serotonin transporter gene promoter polymorphism: evidence from auditory cortical stimulus processing.

BACKGROUND: Cigarette smoking has been associated with mood enhancing properties and modulating effects on serotonin activity. The loudness dependence (LD) of the auditory-evoked N1/P2-component has been related to serotonergic neurotransmission, i. e. the allelic variants in the promoter of the 5-hydroxytryptamine-transporter (5-HTT) gene (SCL6A4). Moreover, smoking behavior has been associated to the 5-HTT-genotype. It was hypothesized that cigarette smoking modulates the LD and this effect was expected to interact with the 5-HTT-genotype. METHODS: 5-HTT-genotype and LD were determined in 63 healthy smokers and 114 nonsmokers. RESULTS: LD was significantly affected by smoking status (p = 0.008) and 5-HTT-genotype (p = 0.045) but not by smoking*genotype-interaction or daily cigarette consumption. Current smokers exhibited a significantly weaker LD compared to nonsmokers. 5-HTT-genotype showed no significant effect on smoking behavior. DISCUSSION: The results indicate a higher serotonergic activity in smokers as compared to nonsmokers independent of 5-HTT-genotype. Since former smokers and never smokers showed similar LDs, the serotonin enhancing effect of smoking seems to be a characteristic state, which may contribute to the maintenance of smoking behavior.