Annemarie Heberlein

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.

BDNF and GDNF serum levels in alcohol-dependent patients during withdrawal.

Preclinical study results suggest that brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) modulate addictive behaviour. Therefore we investigated alterations in BDNF (81 male patients) and GDNF serum levels (52 male patients) in alcohol-dependent patients during alcohol withdrawal (day 1, 7 and 14) in comparison to healthy controls (41 male controls). BDNF serum levels were not significantly altered in alcohol-dependent patients compared to healthy controls (p=0.685). GDNF serum levels were significantly reduced in the alcohol-dependent patients (p<0.001). BDNF (p=0.265) and GDNF (p=0.255) serum levels did not change significantly during alcohol withdrawal. BDNF serum levels were significantly negatively associated with alcohol withdrawal severity on day 1 (CIWA-Ar score, p=0.004). GDNF serum levels were significantly negatively associated with individual estimation of alcohol tolerance (SESA-XT score, p=0.028). There was no further association with psychometric dimensions of alcohol withdrawal. In conclusion we found that GDNF serum levels are significantly reduced in alcohol-dependent patients. GDNF serum levels were negatively associated with alcohol tolerance. Moreover BDNF serum levels were found to be associated with withdrawal severity.

Increased levels of adiponectin and resistin in alcohol dependence—possible link to craving

Recent studies suggested a role of appetite regulating peptides like leptin and ghrelin in alcohol dependence and particularly in the neurobiology of alcohol craving. Aim of the present study was to investigate alterations of the adipocytokines adiponectin and resistin in alcohol-dependent patients. We analyzed a sample of 88 patients at admission for alcohol detoxification and after 1 week of withdrawal treatment in comparison to 89 healthy controls. Adiponectin and resistin serum levels were measured using commercial ELISA kits. The extent of alcohol craving was obtained using the Obsessive Compulsive Drinking Scale (OCDS). Adiponectin and resistin serum levels were significantly elevated in patients with alcohol dependence at both dates (admission and after 1 week of treatment) compared to healthy controls. Adiponectin decreased significantly during the course of withdrawal (T=3.44, p=0.001) while resistin serum levels showed a slight increase (T=-1.83, p=0.071). In a multivariate approach the extent of alcohol craving was significantly associated with adiponectin but not with resistin serum levels in male patients (Beta=-0.255, p=0.025). Results for female patients were not significant. Our findings provide first evidence for an alteration of the adipocytokines adiponectin and resistin during alcohol withdrawal. Furthermore, adiponectin may be involved in the neurobiology of alcohol craving, possibly via its effects on the hypothalamic circuits.

Serum levels of BDNF are associated with craving in opiate-dependent patients

Preclinical study results suggest that brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are involved in the modulation of addictive behaviour. We investigated alterations in serum levels of BDNF and GDNF in opiate-dependent patients (28 males) who received diacetylmorphine treatment within a structured opiate maintenance programme. BDNF (T = 2.735, p = 0.009) serum levels were significantly increased in the opiate-dependent patients as compared with healthy controls (21 males), whereas GDNF serum levels (T = 1.425, p = 0.162) did not differ significantly from GDNF serum levels of the healthy controls. BDNF serum levels were significantly associated with craving for heroin (measured by the Heroin Craving Questionnaire (r = 0.420, p = 0.029) and by the General Craving Scale (r = 0.457, p = 0.016), whereas GDNF serum levels were not associated with psychometric dimensions of heroin craving. In conclusion, our results show a positive association between BDNF serum levels and opiate craving in opiate-dependent patients.

Opioid modulators for alcohol dependence

Introduction: Studies have shown that opioid antagonists like naltrexone are efficient in reducing heavy drinking. The neurobiological mechanism by which opioid modulators affect drinking behavior is based on the strong connection between the endogenous opioid system, the dopamine system and the influence of the CNS stress response. Areas covered: This review provides an overview of the pathophysiological role of the opioid system in alcohol dependence and the neurobiological mechanisms of possible pharmacological interventions. An extensive Medline and Internet research was performed to retrieve information on existing and currently investigated opioid modulators. The findings were assessed critically and interpreted with regard to an individualized therapy for alcohol dependence. Expert opinion: The opioid system is of crucial importance in the genesis and maintenance of alcohol dependence. Naltrexone – and to a lesser extent nalmefene – is an agent that modulates opioidergic transmission in the CNS and it shows a limited but well-studied efficacy in treating alcohol dependence. Several agents (LY2196044, ALKS-29, ALKS-33) that are currently undergoing Phase II and Phase III studies are of interest but first their efficacy must be proved in clinical practice.

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.

The treatment of alcohol and opioid dependence in pregnant women.

Purpose of review This article addresses the question of ‘best treatment options’, which clinicians face when treating pregnant women with alcohol and opioid dependence. Recent findings Studies show that alcohol consumption is associated with fetal abnormalities and long-term cognitive problems depending on the amount consumed, drinking pattern, and time of gestation. Screening and evaluation of specific interventions are important to reduce alcohol consumption during pregnancy and associated problems in infants. Opioid detoxification is only recommended beyond the first trimester and only in those pregnant women who refuse opioid maintenance therapy. Methadone is the most established treatment of pregnant opioid-dependent women, though recent results indicate some advantages of buprenorphine, slow-release oral methadone and diamorphine compared with methadone. Summary Benzodiazepines seem to be the most recommendable option for managing alcohol withdrawal, and psychosocial interventions succeed in reducing alcohol consumption or in maintaining abstinence in alcohol-dependent pregnant women. Regarding opioid dependence, current results suggest that factors like the health status of the mother, the need for additional medications (e.g. treatment for HIV), comorbid drug dependence, and concurrent drug use need to be considered in order to find the ‘best opioid substitute’.

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.

Do changes in the BDNF promoter methylation indicate the risk of alcohol relapse

The neurotrophic growth factor brain derived neurotrophic factor (BDNF) was linked to the risk of alcohol relapse in clinical studies. In this study we investigated alterations in the methylation of the BDNF gene during alcohol withdrawal (day 1, 7 and 14) in 99 male alcohol-dependent patients compared to age matched healthy males (n=33). In particular, we aimed to investigate a possible association between the BDNF promoter methylation and the self-reported duration of alcohol abstinence before relapse. Mean methylation of the BDNF promoter was significantly increased in alcohol-dependent patients compared to the healthy controls (F=10.014, p<0.001) and decreased significantly during alcohol-withdrawal (F=10.014, p<0.001). Moreover, mean methylation was associated with depressive (F=2.014, p<0.001) and anxious symptoms in the alcohol-dependent patients (F=2.228, p<0.001). On day 14 of alcohol-withdrawal we found significantly higher methylation rates in those patients who abstained longer before relapse compared to those patients who abstained shorter (F=9.938, p<0.001). Our results suggest an association between BDNF expression and the symptomatology of alcohol withdrawal and imply that changes in the methylation of the BDNF IV gene may contribute to alcohol consumption.

DNA methylation of the LEP gene is associated with craving during alcohol withdrawal

Different studies have described evidence for an association between leptin serum levels and craving in alcohol dependent patients. As leptin expression is regulated by DNA methylation we investigated changes of DNA methylation of the LEP gene promoter region in alcohol dependent patients undergoing withdrawal. Results show that low methylation status is associated with increasing serum leptin levels and elevation of craving for alcohol in the referring patients group. These findings point towards a pathophysiological relevance of changes in DNA methylation of the LEP gene promoter region in alcohol dependence.