[Moral Competence in Medical Students - Comparison Between First Semester and Practical Year Students]. / Moralische Kompetenz bei Medizinstudierenden ­ Vergleich zwischen Studierenden des ersten Semesters und des Praktischen Jahres.

OBJECTIVE: In addition to teaching theoretical and clinical-practical skills, the development of individual moral competence should be another core concern in medical school. However, research suggests that moral competence in students of human medicine stagnates or even declines during the course of medical school. Therefore, the present cross-sectional study investigated the moral competence of medical students at the beginning of their studies and during their practical year, as well as the effects of testosterone as a neurohormone on moral judgment. METHODS: By means of a cross-sectional study, the moral judgment ability of 24 first-year and 16 practical year students of Hannover Medical School was recorded and evaluated with the Moral Competence Test (MCT) according to Lind. The testosterone serum level of the study participants was statistically related to the MCT results. RESULTS: No significant differences between first-year (mean±standard deviation (SD): 13.16±8.21) and practical year students (mean±SD: 11.24±8.07) with regard to moral competence as per the MCT were identified (p=0.36). Higher serum testosterone levels did not show a statistically significant correlation with moral competence (r=-0.09, p=0.58). CONCLUSION: Our results do not show a clear trend whether moral competence is lower in medical students in advanced semesters compared to the beginning of medical school and whether moral competence is influenced by the neurohormone testosterone. Nevertheless, it seems reasonable to implement moral competence training for medical students early, continuously, and as individually designed as possible during medical school (and to evaluate it in further studies) in order to preventively counteract stagnation or regression of moral judgment.

Association of Testosterone Levels and Steroid 5-Alpha-Reductase 2 Polymorphisms with Opioid Craving.

BACKGROUND/AIMS: Opioid dependence is a severe disease which is associated with a high risk of relapse, even in cases of successful withdrawal therapy. Studies have shown alterations of the hypothalamic-pituitary-gonadal axis in opioid-dependent patients, such as decreased testosterone serum levels in affected males. Sex hormones and the steroid 5-alpha-reductase 2 (SRD5A2) V89L polymorphism are associated with craving during alcohol withdrawal, but little is known about their impact on symptomatology of opioid dependence. METHODS: In this study, we analyzed 2 independent male cohorts of opioid-dependent patients for possible alterations in testosterone serum levels compared to non-opioid-dependent controls. In one of the cohorts, we additionally investigated associations of testosterone serum levels and 3 SRD5A2 polymorphisms with symptoms of opioid dependence, measured by the Heroin Craving Questionnaire (HCQ). RESULTS: In the patient groups, we found significantly decreased testosterone serum levels compared to the control groups. Furthermore, we found significant associations of both the testosterone serum levels and the SRD5A2 V89L polymorphism with opioid craving assessed by the HCQ. CONCLUSION: Our data show a possible role of testosterone metabolism in opioid dependence, which may be relevant for the establishment of future treatment strategies.

Trauma Severity in Early Childhood Correlates with Stress and Satiety Hormone Levels in a Pilot Cohort Receiving Diamorphine Maintenance Treatment.

AIMS: Childhood trauma is of importance for the manifestation of substance-related disorders and maintenance of hypothalamic-pituitary-adrenal (HPA)-axis disorders. Since stress plays a crucial role in opioid compliance and craving, we investigated the immediate effects of diacetylmorphine application on the HPA axis. In particular, adrenocorticotropic hormone (ACTH) and cortisol secretion, as well as satiety regulating proopiomelanocortin peptides α-melanocyte-stimulating hormone (MSH) and ß-endorphin (END) in a cohort of opioid-dependent patients in diamorphine maintenance treatment concerning the clinical severity of their childhood trauma. METHODS: We compared the serum levels of ACTH, cortisol, MSH, and END in 15 opioid-dependent patients. All participants received treatment with diamorphine and were observed at 5 timepoints before and after injection. We split the cohort into 2 subgroups concerning childhood trauma measured by the Childhood Trauma Questionnaire. RESULTS: Splitting in 2 subgroups for mild (5) and severe trauma (10), we found that while both groups show a significant reduction of ACTH and cortisol levels over time, slopes display different progressions over time for cortisol (F[1.6] = 9.38, p = 0.02), while remaining identical for ACTH (F[1.6] = 1.69, p = 0.24). Also, levels of both MSH and END were significantly lower in severely traumatized patients. CONCLUSIONS: For the first time, we present a detailed representation of stress- and addiction-related proteins for the first 5 h after diamorphine application, demonstrating the interrelationship between stress hormones and childhood trauma as well as its potential effects on the progression of addictions such as opioid dependence.

Epigenetic Effects of Intravenous Diacetylmorphine on the Methylation of POMC and NR3C1.

The administration of diacetylmorphine (DAM) reduces the activation of the hypothalamic-pituitary-adrenal (HPA) axis in opioid-maintained patients. However, the epigenetic effects of DAM on addiction-related genes have not been investigated yet. In a randomized controlled study, we examined the immediate effects of intravenous DAM versus placebo on the promoter methylation of the POMC (pro- opiomelanocortin) and NR3C1 (glucocorticoid receptor 1) genes. Twenty-eight heroin-dependent patients on DAM-assisted treatment received either DAM or saline in a randomized crossover design and 17 healthy participants received saline only. EDTA blood samples were taken 25 min before and 10 min after the injection of DAM or saline. We found reciprocal regulation effects for DAM versus saline application regarding the methylation of POMC; while DAM injection significantly increased methylation, saline injection led to a significant decrease in methylation for patients as well as controls. NR3C1 data did not show significant changes in methylation. Injection of DAM blunted stress hormone levels and the POMC promoter methylation of heroin-dependent patients. These findings provide first preliminary insights into the epigenetic mechanisms underlying the emotional regulation effects of DAM-assisted treatment in severe heroin-dependent patients.

Elevated methylation and decreased serum concentrations of BDNF in patients in levomethadone compared to diamorphine maintenance treatment.

Brain-derived neurotrophic factor (BDNF) appears to play a crucial role in the reward response to drugs such as heroin. The primary objective of the present study was to examine epigenetic changes and serum levels of BDNF in patients undergoing different opiate-based maintenance treatments. We compared patients receiving treatment with either levomethadone (n = 55) or diamorphine (n = 28) with a healthy control group (n = 51). When comparing all subjects (patients and controls), BDNF serum levels showed a negative correlation with the BDNF IV promoter methylation rate (r = -0.177, p = 0.048). Furthermore, BDNF serum levels negatively correlated with Beck's Depression Inventory measurements (r = -0.177, p < 0.001). Patients receiving diamorphine maintenance treatment showed slightly decreased BDNF serum levels compared to healthy controls, whereas patients on levomethadone maintenance treatment with or without heroine co-use showed a pronounced decrease (analysis of covariance: control vs. levomethadone with and without heroine co-use: p < 0.0001, diamorphine vs. levomethadone with heroine co-use: p = 0.043, diamorphine vs. levomethadone without heroine co-use: p < 0.0001). According to these findings, methylation of the BDNF IV promoter showed the highest level in patients receiving levomethadone without heroine co-use (linear mixed model: control vs. levomethadone group without heroine co-use: p = 0.008, with heroin co-use: p = 0.050, diamorphine vs. levomethadone group with heroine co-use: p = 0.077 and without heroine co-use: p = 0.015.). For the first time, we show an epigenetic mechanism that may provide an explanation for mood destabilization in levomethadone maintenance treatment.

Promoter Polymorphism rs886205 Genotype Interacts With DNA Methylation of the ALDH2 Regulatory Region in Alcohol Dependence.

AIMS: Aldehyde dehydrogenase 2 (ALDH2) protects cells from ethanol toxicity by metabolizing acetaldehyde. We studied the single nucleotide polymorphism (SNP) rs886205s located between a negative and a positive regulating promoter element in the ALDH2 gene. The negative regulatory region was already associated with differential DNA methylation in the two allele variations of rs886205 SNP. Another CpG island, in the positive regulatory region of the ALDH2 promoter, extends through the SNP rs886205 and a nuclear receptor response element. METHODS: We assessed rs886305 genotype and DNA methylation using bisulfite sequencing in a cohort of 83 male alcohol-dependent patients undergoing detoxification treatment (Days 1, 7 and 14) and in 33 male age-matched controls. Luciferase reporter assays were performed to address the functional significance of genotype and methylation. RESULTS: We observed a higher methylation in alcohol-dependent patients compared to controls. Patients with AA (n = 52) or GG/GA (n = 31) genotype differed significantly in baseline methylation levels as well as in methylation kinetics during withdrawal. AA carriers display an increase in methylation from low baseline levels while GG/GA showed the inverse pattern. The reporter gene assays corroborate these data by showing a significant effect of genotype on ALDH2 expression as well as an interaction between genotype and methylation. CONCLUSION: Our results describe a new regulatory role of rs886205 in the methylation of ALDH2 promoter region and provide additional insight into the complex regulation of ALDH2 under the condition of alcohol dependence. SHORT SUMMARY: Genetic variations have been described to influence DNA promoter methylation of various genes. We investigated the association between the polymorphism rs886205, located on ALDH2 promoter and methylation kinetics of the neighboring CpG island in alcohol-dependent patients. Luciferase reporter assays showed functional significance of genotype, methylation and a genotype-epigenotype interaction in vitro.

Joint Effects of the Epigenetic Alteration of Neurotrophins and Cytokine Signaling: A Possible Exploratory Model of Affective Symptoms in Alcohol-Dependent Patients?

AIMS: Neurotrophins have been linked to the symptomatology of alcohol dependence. We aimed to investigate a possible association between the methylation of the promoters of both neurotrophins, the serum levels of the cytokines and core symptoms of alcohol dependence as withdrawal severity and anxiety. METHODS: In this study we investigated a possible association between alterations in the methylation of the BDNF IV/NGF I gene promoter and the cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) in 55 male alcohol-dependent patients. RESULTS: Mean methylation of the promoter of the BDNF gene was significantly associated with the TNF-α serum levels and the CIWA-score during withdrawal (P < 0.001). Moreover, mean methylation of the NGF I promoter was significantly associated with the IL-6 serum levels and STAI-I score during withdrawal (P < 0.001). CONCLUSION: Our results suggest an association between the epigenetic regulation of both neurotrophins, BDNF and NGF, cytokine release and the symptomatology of alcohol dependence. They imply that changes in the methylation of neurotrophins may contribute to the symptomatology of alcohol dependence by affecting relevant downstream signaling cascades.

Epigenetic Regulation of the Promotor Region of Vascular Endothelial Growth Factor-A and Nerve Growth Factor in Opioid-Maintained Patients.

AIMS: The nerve growth factor (NGF) and the vascular endothelial growth factor-A (VEGF-A) may be of importance for psychiatric diseases including substance use disorders. The aim of the study was to identify differences in the regulation of both neuropeptides via the DNA-methylation status of the promotor regions of NGF and VEGF-A in different forms of maintenance therapy for opioid dependence and the related stress regulation via the hypothalamic-pituitary-adrenal axis. METHODS: We compared methylation levels of opioid-dependent patients receiving treatment with diamorphine (n = 28) or levomethadone (n = 54) and similar levels in a healthy control group (n = 72). RESULTS: There was a significantly higher methylation of VEGF-A in opioid-maintained patients with levomethadone compared to that in the control group (estimated marginal means [EMM] [SE]): 0.036 [0.003] vs. 0.020 [0.003]; p < 0.001). We performed a cluster analysis for NGF, splitting up the results in 4 clusters. We found significant changes in methylation rates of the opioid-maintained patients compared to the controls in cluster I ([EMM] [SE]: 0.064 [0.005] vs. 0.084 [0.006]; p = 0.03), cluster II ([EMM] [SE]: 0.133 [0.013] vs. 0.187 [0.014]; p < 0.001) and cluster III ([EMM] [SE]: 0.190 [0.014] vs. 0.128 [0.016]; p < 0.001). CONCLUSIONS: The results are of importance, as they indicate that long-term changes in stress regulation regulated by neurotrophines are a crucial part of the symptomatology of opioid dependence, thus influencing drug consumption and the different forms of opioid-maintenance therapies.

The Epigenetic Regulation of GATA4-Dependent Brain Natriuretic Peptide Expression during Alcohol Withdrawal.

OBJECTIVE: Natriuretic peptides participate in the collection of metabolic effects during alcohol withdrawal. Having witnessed modulation of other natriuretic peptides in alcohol-dependent patients during alcohol withdrawal, we were interested in the relation of brain natriuretic peptide (BNP) methylation with protein expression and craving in this longitudinal study. METHODS: Ninety-nine male patients were compared to 101 healthy controls concerning epigenetic regulation and protein expression during detoxification treatment. RESULTS: With BNP expression being GATA4 dependent, we observed a correlation of GATA4 binding site methylation and protein expression. BNP serum levels and Obsessive Compulsive Drinking Scale scores are significantly decreased during withdrawal. Focusing on the two CpGs that are between GATA transcription factor binding sites, statistical analysis revealed a reversely proportional methylation pattern, significantly increasing with ongoing detoxification and thereby supporting the observed serum level changes. CONCLUSION: Without the functional knowledge about regulation of BNP expression via the GATA transcription factor, it would have been easy to take the mean results of the global CpG data and propose a direct relationship between methylation and expression. Thus, these findings are a voice for functionally and mechanistically approved results. There was no causal relationship between protein expression levels and epigenetic changes. Further research is needed which includes protein expression and other approaches.

Impaired Regulation of ALDH2 Protein Expression Revealing a Yet Unknown Epigenetic Impact of rs886205 on Specific Methylation of a Negative Regulatory Promoter Region in Alcohol-Dependent Patients.

Acetaldehyde, the carcinogenic metabolite of ethanol known to provoke aversive symptoms of alcohol consumption, is predominantly eliminated by aldehyde dehydrogenase 2 (ALDH2). Reduced ALDH2 activity correlates with low alcohol tolerance and low risk for alcohol dependence. The ALDH2 promoter polymorphism rs886205 (A>G) is associated with decreased promoter activity, but a molecular mechanism and allele-dependent ALDH2 protein expression has not been described yet. On the basis of allele-dependent epigenetic effects, we analyzed the rs886205 genotype, methylation rates of cytosine-phosphatidyl-guanine (CpG)-sites within a regulatory promoter region and ALDH2 protein levels in 82 alcohol-dependent patients during a 2-week withdrawal and compared them to 34 matched controls. Patients without the G-allele of rs886205 showed higher methylation of the promoter region than controls and readily adapted epigenetically as well as on protein level during withdrawal, while patients with the G-allele displayed retarded methylation readjustment and no change in ALDH2 protein levels. Our data provide novel insights into an unknown genetic-epigenetic interaction, revealing impaired ALDH2 protein expression in patients with the G-allele of rs886205. Additionally, we checked for an association between rs886205 and protection against alcohol dependence and found a trend association between the G-allele and protection against alcohol dependence that needs replication in a larger Caucasian cohort.

BDNF serum levels and promoter methylation of BDNF exon I, IV and VI in depressed patients receiving electroconvulsive therapy.

We examined potential changes in brain-derived neurotrophic factor (BDNF) serum levels and promoter methylation of the BDNF gene in 11 patients with treatment-resistant major depressive disorder during a series of electroconvulsive therapy (ECT). Blood samples were taken before, 1 and 24 h after ECT treatment sessions 1, 4, 7 and 10. Patients remitting under ECT had significantly lower mean promoter methylation rates, especially concerning the exon I promoter, compared to non-remitters (both p < 0.002). These findings may point to a depression subtype in which ECT is particularly beneficial.

Serial repetitive transcranial magnetic stimulation (rTMS) decreases BDNF serum levels in healthy male volunteers.

Although repetitive transcranial magnetic stimulation (rTMS) is established in the treatment of depression, there is little knowledge about the underlying molecular mechanisms. In the last decade, the neurotrophic hypothesis of depression entailed a plethora of studies on the role of neurogenesis-associated factors in affective disorders and rTMS treatment. In the present study, we hypothesised a sham-controlled increase of peripheral brain-derived neurotrophic factor (BDNF) levels following serial rTMS stimulations in healthy individuals. We investigated the influence of a cycle of nine daily high-frequency (HF)-rTMS (25 Hz) stimulations over the left dorsolateral prefrontal cortex (DLPFC) on serum levels of BDNF in 44 young healthy male volunteers. BDNF serum concentrations were measured at baseline, on day 5 and on day 10. Overall, the statistical analyses showed that the active and sham group differed significantly regarding their responses of BDNF serum levels. Contrary to our expectations, there was a significant decrease of BDNF only during active treatment. Following the treatment period, significantly lower BDNF serum levels were quantified in the active group on day 10, when compared to the sham group. The participants' smoking status affected this effect. Our results suggest that serial HF-rTMS stimulations over the left DLPFC decrease serum BDNF levels in healthy male volunteers. This provides further evidence for an involvement of BDNF in clinical rTMS effects.

Alcohol-induced changes in methylation status of individual CpG sites, and serum levels of vasopressin and atrial natriuretic peptide in alcohol-dependent patients during detoxification treatment.

Disturbances of volume-regulating peptides like vasopressin (AVP) and atrial natriuretic peptide (ANP) have been described in early abstinent alcohol-dependent patients. In a longitudinal approach, we investigated whether changes in AVP and ANP serum levels correlated to cytosine-phosphatidyl-guanine (CpG) methylation of the respective gene promoters on days 1, 7 and 14 of alcohol withdrawal. We analyzed the blood samples of 99 patients suffering from alcohol dependence alongside age- and BMI-matched controls. Concerning AVP promoter methylation, we observed an interaction between time of measurement and CpG loci with CpG 2 showing a significant increase in methylation from day 1 to 14. Serum levels of AVP were significantly decreased in the patient group. Compared to healthy controls, promoter-related DNA methylation of the ANP promoter was significantly reduced on days 7 and 14. Moreover, we detected a significant interaction between CpG position and group. In both cases the difference was mainly observed at CpG 1. The present study shows significant changes in the methylation status of individual CpG sites of AVP and ANP. Observing respective alterations of AVP serum protein levels in alcohol-dependent patients during detoxification treatment, we consider methylation as a possible mode of regulation for these proteins during alcohol detoxification.

Atrial natriuretic peptide, arginine vasopressin peptide and cortisol serum levels in opiate-dependent patients.

Preclinical studies suggest that chronic drug abuse profoundly alters stress-responsive systems. The best studied of the stress-responsive systems in humans is the hypothalamic-pituitary-adrenal (HPA) axis. Apart from cortisol, arginine vasopressin peptide (AVP), and atrial natriuretic peptide (ANP) are known to directly impact upon the HPA axis in addictive behavior. We investigated alterations in ANP, AVP and cortisol serum levels in opiate-dependent patients who received diacetylmorphine treatment within a structured opiate maintenance program. ANP serum levels were significantly increased in opiate-dependent patients as compared to healthy controls, whereas AVP and cortisol serum levels were reduced. The ANP, AVP and cortisol serum levels were not significantly associated with the psychometric dimensions of heroin craving. In conclusion, chronic drug abuse profoundly alters stress-responsive systems like the HPA axis. Alterations of AVP, ANP and cortisol appear to constitute an important component in the neurobiology of opiate-dependent patients.

Epigenetic down regulation of nerve growth factor during alcohol withdrawal.

We investigated the Cytosin-phosphatidyl-Guanin (CpG) island promoter methylation (mean and methylation of individual CpG-sites) of the nerve growth factor (NGF) gene in the blood of alcohol-dependent patients (57 male patients) during withdrawal (days 1, 7 and 14). Methylation and NGF serum levels did not change significantly from days 1-7. From days 7-14, mean methylation increased (F = 30.55, P < 0.001), whereas the NGF serum levels decreased significantly (days 7-14: F = 17.95, P < 0.001). The NGF serum levels were significantly associated with the mean methylation of the investigated CpG-sites (F = 1.55, P < 0.001). These results imply an epigenetic regulation of the NGF gene during alcohol withdrawal.

Indicators for elevated risk factors for alcohol-withdrawal seizures: an analysis using a random forest algorithm.

Alcohol-withdrawal seizures (AWS) are an important and relevant complication during detoxification in alcohol-dependent patients. Therefore, it is important to evaluate the individual risk for AWS. We apply a random forest algorithm to assess possible predictive markers in a large sample of 200 alcohol-dependent patients undergoing alcohol withdrawal. This analysis showed that the combination of homocysteine, prolactin, blood alcohol concentration on admission, number of preceding withdrawals, age and the number of cigarettes smoked may successfully predict AWS. In conclusion, the results of this analysis allow for origination of further research, which should include additional biological and psychosocial parameters as well as consumption behaviour.

Alterations of homocysteine serum levels during alcohol withdrawal are influenced by folate and riboflavin: results from the German Investigation on Neurobiology in Alcoholism (GINA).

AIMS: Various studies have shown that plasma homocysteine (HCY) serum levels are elevated in actively drinking alcohol-dependent patients a during alcohol withdrawal, while rapidly declining during abstinence. Hyperhomocysteinemia has been associated not only with blood alcohol concentration (BAC), but also with deficiency of different B-vitamins, particularly folate, pyridoxine and cobalamin. METHODS: Our study included 168 inpatients (110 men, 58 women) after admission for detoxification treatment. BAC, folate, cobalamin, pyridoxine, thiamine and riboflavin were obtained on admission (Day 1). HCY was assessed on Days 1, 7 and 11. RESULTS: HCY levels significantly declined during withdrawal. General linear models and linear regression analysis showed an influence of BAC, folate and riboflavin on the HCY levels on admission as well as on HCY changes occurring during alcohol withdrawal. No significant influence was found for thiamine, cobalamin and pyridoxine. CONCLUSIONS: These findings show that not only BAC and plasma folate levels, but also plasma levels of riboflavin influence HCY plasma levels in alcohol-dependent patients.

Biological markers for alcohol withdrawal seizures: a retrospective analysis.

AIMS: Alcohol withdrawal seizures (AWS) are among the most important possible complications during the detoxification treatment of alcohol-dependent patients. Pharmacological therapy is often used during detoxification, but can cause dangerous side effects [Eur Addict Res 2010;16:179-184]. In separate studies several biological markers have been described as being associated with AWS risk. We investigated the role of homocysteine (HCT), carbohydrate-deficient transferrin (CDT) and prolactin (PRL) as biological markers for the risk of developing AWS. METHODS: The present study included 189 alcohol-dependent patients of whom 51 had a history of AWS. We investigated the HCT, CDT and PRL levels of all patients and calculated sensitivity and specificity. Bayes' theorem was used to calculate positive (PPV) and negative (NPV) predictive values. RESULTS: The highest combined sensitivity and specificity for %CDT was reached at a plasma cutoff value of 3.75%. The combination of HCT at a cutoff value of 23.9 µmol/l and %CDT at a cutoff value of 3.75% showed the best predictive values (sensitivity 47.1%, specificity 88.4%, PPV 0.504, NPV 0.870). CONCLUSION: A combined assessment of HCT and CDT levels can be a useful method to identify patients at a higher risk of AWS, which may lead to a more individualized therapy.

Association of nerve growth factor and vascular endothelial growth factor A with psychometric measurements of opiate dependence: results of a pilot study in patients participating in a structured diamorphine maintenance program.

Preclinical study results suggest that neurotrophic peptides like nerve growth factor (NGF) and vascular endothelial growth factor A (VEGF-A) may be associated with symptoms of addictive behavior like withdrawal symptoms and rewarding effects. We investigated alterations in NGF and VEGF-A serum levels in opiate-dependent patients (25 male patients), who received diamorphine (DAM, heroin) treatment within a structured opiate maintenance program, and compared the results with the NGF and VEGF-A serum levels of healthy controls (23 male controls). NGF and VEGF-A serum levels were assessed before and after DAM administration twice a day (in the morning (16 h after last application--t1) and in the afternoon (7 h after last application--t3)) in order to detect a possible immediate or summative (in the afternoon) heroin effect on these two neuropeptides. Moreover, we investigated possible associations between the serum levels of these neurotrophic growth factors and psychometric dimensions of addictive behavior, e.g. craving, withdrawal, depression. Whereas there was no direct effect of DAM application on the serum levels of both neurotrophic growth factors neither in the morning nor in the afternoon, the NGF serum levels of the patient group were found to be significantly increased at all four time points of investigation compared with the healthy controls. In contrast, VEGF-A serum levels did not differ significantly in the patient and control groups. We found a significant positive association between the NGF serum levels and several items of the short opiate withdrawal scale as well as a negative association between self-reported mood (measured by visual analogue scale) and mood before heroin application (in the morning as in the afternoon). Moreover, we found a significant positive association between the NGF serum levels (t1 and t3) and the self-reported craving for methadone. In contrast, we found a negative association between the VEGF-A serum levels and avoidance, anxiety, suicide intentions of the SCL-90 as well as a positive association between the VEGF-A serum levels and the subscales of the heroin craving questionnaire measuring the rewarding effects of heroin. In conclusion, the results of this pilot study show that there might be an association between symptoms of opiate dependence and withdrawal and serum levels of VEGF-A and NGF.

Prolactin serum levels during alcohol withdrawal are associated with the severity of alcohol dependence and withdrawal symptoms.

BACKGROUND: Prolactin serum levels have been described to be elevated during alcohol withdrawal in alcohol-dependent patients and normalize during abstinence. Alterations in prolactin levels may reflect disturbances of dopaminergic neurotransmission which is of crucial importance for alcohol-seeking behavior. METHODS: In this longitudinal observational study, we investigated prolactin serum levels in 99 male patients during the first 14 days of alcohol withdrawal and early abstinence and in 43 healthy controls. To assess the severity of alcohol dependence, the extent of withdrawal symptoms, craving, depressive symptoms, and anxiety, we employed a structured interview including psychologic measurements. RESULTS: Prolactin serum levels were elevated during the whole study period in alcohol-dependent patients compared to the healthy control group. Prolactin levels at admission (first day of alcohol withdrawal) were associated with the severity of alcohol withdrawal (CIWA-Ar) and of alcohol dependence (SESA) but not with the other assessed psychologic parameters. CONCLUSIONS: The presented findings confirm that prolactin is significantly elevated in alcohol-dependent patients during alcohol withdrawal and early abstinence, not showing a rapid decline after cessation of drinking. The association with the severity of withdrawal and dependence may reflect at least partially the individual alterations in the dopaminergic and glutamatergic pathways.