Nalmefene for treatment of alcohol dependence

 

Alcohol use and dependence are frequent disorders. Despite numerous established psychosocial approaches, relapse to heavy drinking is common in alcohol-dependent patients after detoxification and relapse prevention remains a significant medical challenge.

The opioidergic system plays a crucial role in mediating the rewarding effects of alcohol, in part by modulating dopaminergic neurotransmission in mesolimbic brain areas.

This review will discuss the neurochemical basis of alcoholism with respect to the opiodergic system. Nalmefene is an alternate opioid receptor that also targets the kappa opioid receptors and thus offers a different treatment approach. The treatment studies conducted so far are discussed.

We present a comprehensive overview of the implication of the opioidergic system in mediating the rewarding effects of alcoholism and the preclinical and clinical studies conducted so far with nalmefene.

Although the number of clinical studies conducted with naltrexone by far exceeds the number conducted with nalmefene, the four studies on nalmefene published so far may indicate a role of this opioid antagonist in the treatment of alcoholism.

Results of some ongoing studies on nalmefene will provide additional data on its use for this indication.

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Request Reprint E-Mail: Susanne.Roesner@med.uni-muenchen.de   

NIAAA Director's Report on Institute Activities to the 125th Meeting of the National Advisory Council on Alcohol Abuse and Alcoholism - September 23, 2010

Contents

A.  Legislation, Budget, and Policy	F. News Media Interactions
B. Director's Activities	G. NIAAA Staff and Organization
C. Staff Honors	H. What's Ahead
D. Press Releases	I. NIAAA Program Annoucement and Request for Applications Information
E. Multi-Media Products	J. NIAAA Research Programs

Immunoglobulin-E reactivity to wine glycoproteins in heavy drinkers

N-glycans from plant and invertebrate allergens can induce extensive immunoglobulin-E (IgE) cross-reactivity in vitro. IgE antibodies against these N-glycans, also termed cross-reactive carbohydrate determinants or CCDs, are prevalent in alcohol drinkers.

This study investigated the prevalence and biological significance of IgE antibodies to N-glycans from wine glycoproteins in heavy drinkers.

A structured questionnaire, skin prick tests, serum IgE levels, IgE-immunoblotting to wine extracts, and basophil activation tests were used to characterize 20 heavy drinkers and 10 control subjects.

Eleven heavy drinkers (55%) showed IgE binding to proteins in wine extracts. The proteins were identified by mass spectrometry as grape-derived vacuolar invertase and thaumatin-like protein. Immunoblot reactivity was closely associated with the presence of IgE to CCDs and was inhibited by preincubation with a glycoconjugate containing bromelain-type N-glycans.

The same conjugate, CCD-bearing allergens, and wine extracts activated basophils in patients with high-titer CCD-specific IgE but not in healthy controls.

There was no relationship between immunoblot reactivity and consumption of any specific type of wine.

No patient reported symptoms of hypersensitivity to Hymenoptera venom, food, or wine.

In conclusion, heavy drinkers frequently show IgE reactivity to the N-glycans of wine glycoproteins.

Glycans and wine glycoprotein extracts can induce basophil activation in sensitized alcoholics. 

The clinical significance of these findings remains to be elucidated.

 
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Request Reprint E-Mail:  arturo.gonzalez.quintela@usc.es 

Temporal and spatial patterns in the rate of alcohol withdrawal syndrome in a defined community

There is a paucity of data about the epidemiology of alcohol withdrawal syndrome (AWS) and, particularly, with regard to temporal trends and sociodemographic factors.

This study included 7,195 episodes of AWS in a defined community (Galicia, Spain) over a 11-year period. We looked for geographical correlations between AWS rate and sociodemographic factors (education and socioeconomic levels and rates of occupational activity and unemployment) within respective districts. We also investigated the inter- and intra-annual time trends for AWS.

The median age of the participants was 49 years (interquartile range, 41–60 years), and 85% were men. 

The annual frequency of AWS episodes remained stable during the study period, with a consistent peak in episodes during the summer months and lowest frequency of episodes in winter months.

The age- and sex-adjusted geographical distribution of the AWS rate was uneven; districts with high rate tended to cluster.

The mean education level was negatively correlated with AWS rate within a given district after adjusting for socioeconomic level, occupational activity rate, and unemployment rate.

In conclusion, we identified characteristic temporospatial patterns of AWS rate in this defined community. The rate of AWS tended to be higher in the summer months and lower in the winter months. The rate of AWS was higher in districts with low education levels.

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Request Reprint E-Mail: arturo.gonzalez.quintela@usc.es  

Overexpression of 5-HT1B mRNA in nucleus accumbens shell projection neurons differentially affects microarchitecture of initiation and maintenance of ethanol consumption

Serotonin 1B (5-HT1B) heteroreceptors on nucleus accumbens shell (NAcSh) projection neurons have been shown to enhance the voluntary consumption of alcohol by rats, presumably by modulating the activity of the mesolimbic reward pathway.

The present study examined whether increasing 5-HT1B receptors expressed on NAcSh projection neurons by means of virus-mediated gene transfer enhances ethanol consumption during the initiation or maintenance phase of drinking and alters the temporal pattern of drinking behavior.

Animals received stereotaxic injections of viral vectors expressing either 5-HT1B receptor and green fluorescent protein (GFP) or GFP alone. Home cages equipped with a three-bottle (water and 6 and 12% ethanol) lickometer system recorded animals’ drinking behaviors continuously, capturing either initiation or maintenance of drinking behavior patterns.

Overexpression of 5-HT1B receptors during initiation increased consumption of 12% ethanol during both forced-access and free-choice consumption. There was a shift in drinking pattern for 6% ethanol with an increase in number of drinking bouts per day, although the total number of drinking bouts for 12% ethanol was not different.

Finally, increased 5-HT1B1B receptors facilitate longer drinking bouts of more modest volumes.

Taken together, these results indicate that 5-HT1B receptors expressed on NAcSh projection neurons facilitate ethanol drinking, with different effects during initiation and maintenance of ethanol-drinking behavior.

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Request Reprint E-Mail:  amyfuray@uw.edu    

Assessment of GABA-B, metabotropic glutamate, and opioid receptor involvement in an animal model of binge drinking

Drinking to intoxication or binge drinking is a hallmark characteristic of alcohol abuse. Although hard to model in rodents, the scheduled high alcohol consumption (SHAC) procedure generates high, stable ethanol intake and blood ethanol concentrations in mice to levels consistent with definitions of binge drinking.

The purpose of the present studies was to determine the effects of pharmacological manipulation of the opioidergic, glutamatergic, and γ-aminobutyric acid (GABA)ergic systems on binge drinking with the SHAC procedure.

Parallel manipulations were conducted in mice trained in operant self-administration of either sucrose or ethanol. For the SHAC procedure, genetically heterogeneous Withdrawal Seizure Control mice were given varying periods of fluid access, with a 30-min ethanol session every third day (total of seven).

Mice were pretreated intraperitoneally with naltrexone (0, 0.6, or 1.25mg/kg), baclofen (0, 2.5, or 5.0mg/kg), or 2-methyl-6-(phenylethynyl)-pyridine (MPEP; 0, 3.0, or 10.0mg/kg) before each ethanol session. 

For the operant self-administration procedure, separate groups of C57BL/6 mice were trained to complete a single response requirement (16 presses on the active lever) to gain 30min of access to an ethanol or a sucrose solution. Mice received pretreatments of the same doses of naltrexone, MPEP, or baclofen before the self-administration sessions, with saline injections on intervening days.

Naltrexone produced a dose-dependent decrease in binge drinking, and the highest dose also significantly decreased operant self-administration of ethanol and sucrose.

Both doses of baclofen significantly decreased binge alcohol consumption, but the higher dose also tended to decrease water intake. The highest dose of baclofen also significantly decreased operant self-administration of sucrose. MPEP (10mg/kg) significantly decreased binge alcohol consumption and sucrose self-administration

These results indicate that manipulation of the opioidergic, glutamatergic, and GABAergic systems significantly decreased binge drinking.

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Ethanol-induced downregulation of the angiotensin AT2 receptor in murine fibroblasts is mediated by PARP-1

Molecular mechanisms accompanying ethanol-induced cytotoxicity remain to be defined.

The renin–angiotensin system with its respective receptors, the angiotensin AT1 and AT2 receptor (AT1R and AT2R), has been implicated in these processes. The AT2R seems to counteract the pro-inflammatory, pro-hypertrophic, and pro-fibrotic actions of the AT1R and is involved in cellular differentiation and tissue repair.

Recently, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a novel negative transcriptional regulator of the AT2R.  However, the complex interactions between ethanol, PARP-1, and the AT2R are largely unknown.

In this in vitro study, we aimed to clarify whether acute ethanol treatment modifies AT2R promoter activity or AT2R mRNA and protein levels and whether PARP-1 is involved in ethanol-mediated regulation of the AT2R.

Murine fibroblasts of the R3T3 and MEF line (murine embryonic fibroblasts) were exposed to ethanol for 24h. AT2R promoter activity, mRNA and protein levels were analyzed with and without PARP-1 inhibition and in PARP-1 knockout MEF cells. Expression of PARP-1 was analyzed over course of time, and cell viability and DNA fragmentation were measured on single-cell level by flow cytometry.

Ethanol exposition induced substantial downregulation of the AT2R on promoter, mRNA and protein levels in a dose-dependent manner. Pharmacological inhibition or ablation of PARP-1 completely abolished this effect.

Ethanol treatment did not have any effect on AT1R mRNA and protein levels in MEF cells.

Further, acute ethanol treatment promoted DNA fragmentation and caused transcriptional induction of PARP-1.

Our findings reveal that PARP-1 is an upstream transcriptional regulator of the AT2 receptor in the context of ethanol exposure and represses the AT2R gene in fibroblasts in vitro.

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Request Reprint E-Mail:  mario.menk@charite.de

Variations in expression of the potentially tissue-protective AT2R might contribute to ethanol-mediated pathology.

Effects of prolonged ethanol vapor exposure on forced swim behavior, and neuropeptide Y and corticotropin-releasing factor levels in rat brains

Depressive symptoms in alcohol-dependent individuals are well-recognized and clinically relevant phenomena. The etiology has not been elucidated although it is clear that the depressive symptoms may be alcohol independent or alcohol induced.

To contribute to the understanding of the neurobiology of chronic ethanol use, we investigated the effects of chronic intermittent ethanol vapor exposure on behaviors in the forced swim test (FST) and neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) levels in specific brain regions.

Adult male Wistar rats were subjected to intermittent ethanol vapor (14h on/10h off) or air exposure for 2 weeks and were then tested at three time points corresponding to acute withdrawal (8–12h into withdrawal) and protracted withdrawal (30 and 60 days of withdrawal) in the FST. The behaviors that were measured in the five-min FST consisted of latency to immobility, swim time, immobility time, and climbing time.

The FST results showed that the vapor-exposed animals displayed depressive-like behaviors; for instance, decreased latency to immobility in acute withdrawal and decreased latency to immobility, decreased swim time and increased immobility time in protracted withdrawal, with differences between air- and vapor-exposed animals becoming more pronounced over the 60-day withdrawal period.

NPY levels in the frontal cortex of the vapor-exposed animals were decreased compared with the control animals, and CRF levels in the amygdala were correlated with increased immobility time.

Thus, extended ethanol vapor exposure produced long-lasting changes in FST behavior and NPY levels in the brain.

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Request Reprint E-Mail:   b_walker@wsu.edu

Fine mapping and expression of candidate genes within the chromosome 10 QTL region of the high and low alcohol-drinking rats

The high and low alcohol-drinking (HAD and LAD) rats were selectively bred for differences in alcohol intake.

The HAD/LAD rats originated from the N/Nih heterogeneous stock developed from intercrossing eight inbred rat strains.

The HAD×LAD F2 were genotyped, and a powerful analytical approach, using ancestral recombination and F2 recombination, was used to narrow a quantitative trait loci (QTL) for alcohol drinking to a 2-cM region on distal chromosome 10 that was in common in the HAD1/LAD1 and HAD2/LAD2 analyses.

Quantitative real-time PCR was used to examine mRNA expression of six candidate genes (Crebbp, Trap1, Gnptg, Clcn7, Fahd1, and Mapk8ip3) located within the narrowed QTL region in the HAD1/LAD1 rats.

Expression was examined in five brain regions, including the nucleus accumbens, amygdala, caudate putamen, hippocampus, and prefrontal cortex.

All six genes showed differential expression in at least one brain region.

Of the genes tested in this study, Crebbp and Mapk8ip3 may be the most promising candidates with regard to alcohol drinking.

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Request Reprint E-Mail:  pbice@iupui.edu 

Generation alcohol: is drinking damaging childhood? 2 November 2010, London

The trend for drinking at home has risen sharply in recent years. What does this mean for parents and their children? Youth drinking and the generational impact of parental drinking are two ongoing issues of concern to treatment providers, politicians and the public. Alcohol Concern’s flagship event of the year will hear from academics, experts and politicians on what needs to be done to protect children from alcohol harm.

Event:

Generation alcohol: Is drinking damaging childhood?

Start Date:

Tuesday 02 November 2010

Start Time:

10.00am (9.30am for AGM)

End Time:

4.45pm

Location:

London

Conference  Webpage

Future for alcohol policy? DDN article September 2010

This month's Drink & Drugs News (DDN) features an article exploring the future for alcohol policy given the significant changes facing the field. The comment explores the possible threats and opportunities for alcohol as it seeks to find its voice within wider substance misuse and public health agendas.   > > > >

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KBS 2011 - 37th Annual Alcohol Epidemiology Symposium of the Kettil Bruun Society

The principal aims of the KBS are to instigate further social, epidemiological, and cross-cultural research on alcohol use, to promote the exchange of scientific knowledge and experiences among researchers from various disciplines and to encourage international collaboration. The comparison of social and epidemiological developments found in different countries makes it possible to disentangle major trends from underlying patterns of alcohol use. This is particularly useful for the development of effective strategies to regulate alcohol use - an aspect which is of great interest in many countries.

The primary purpose of the symposium is to provide a forum where researchers involved in studies on alcohol can exchange ideas about their ongoing research. The scope of the symposium includes studies of determinants and consequences of drinking, drinking practices, attitudes and the social and institutional responses to drinking related harms. Empirical research, theoretical papers and reviews of the literature are welcome. Epidemiology is broadly construed and includes research in a variety of disciplines, such as psychology, sociology, criminology, economics, history and other disciplines.

Conference Webpage

Age Differences in Long-Term Patterns of Change in Alcohol Consumption Among Aging Adults

To estimate patterns of long-term, within-person, changes in alcohol consumption among adults of different ages and assess key predictors of alcohol-use patterns over time.

 

Data came from 3,617 adults, interviewed up to four times between 1986 and 2002. Multilevel multinomial logit models estimated the odds of abstinence and heavy drinking relative to moderate drinking.

 

The odds of abstinence increased and the odds of heavy drinking decreased during the study period. Older adults experienced faster increases in abstinence than younger adults. However, data extrapolations suggest that current younger adults are more likely to be abstinent and less likely to be heavy drinkers during late life than current older adults. Time-varying health, social, and lifestyle factors account for some of these patterns.

 

Drinking behavior in our aging population appears to be on a relatively promising course, perhaps reflecting the effectiveness of public health efforts. 


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Request Reprint E-Mail:  bashaw@uamail.albany.edu  

 

Tightening The Genotype-Phenotype Gap: From Genetic Variation to Gene Function

Event:	Ancillary Symposium entitled "Tightening The Genotype-Phenotype Gap: From Genetic Variation to Gene Function"
Location:	60th Annual Meeting of the American Society of Human Genetics (ASHG) at the Walter E. Washington Convention Center, 801 Mount Vernon Place, NW, Washigton, DC 20001-3614.
Start Date:	11/2/2010 8:00 AM
End Date:	11/2/2010 5:30 PM
Event:	Program         Agenda

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The Potential of Recovery Capital

This short paper outlines the concept of recovery capital and discusses the impact that the accumulation of individual success has on groups and communities. 

It seeks to define recovery capital, to capture its flavour and principles, and to look at the intrinsically social forces that are at play in shaping change and in growing communities of recovery.

It also outlines how we will be taking forward these ideas in our action research.

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The effect of risky alcohol use and smoking on suicide risk: findings from the German MONICA/KORA-Augsburg Cohort Study

Smoking and heavy alcohol use predicts suicidal behaviour. Whether the simultaneous presentation of both conditions induces an amplified effect on risk prediction has not been investigated so far.

 

In a community-based cohort study, a total of 12,888 subjects (6,456 men, 6,432 women; age range of 25–74 years at assessment) from three independent population-based cross-sectional MONICA surveys (conducted in 1984/85, 1989/90, and 1994/95), representative for the Southern German population, was followed up until 31 December 2002. Standardized mortality ratios (SMR) for deaths from suicide using German population rates were calculated for smoking and high alcohol consumption. 

 

After a mean follow-up time of 12.0 (SD 4.4) years and 154,275 person-years at risk, a total of 1,449 persons had died from all causes and 38 of them from suicide. Compared to the general population, mortality from suicide was increased for risky alcohol consumption (SMR = 2.37; 95% CI 1.14–4.37) and for smoking (SMR = 2.30; 95% CI 1.36–3.63). A substantial increase in suicide mortality (SMR = 4.80; 95% CI 2.07–9.46) was observed for smokers with risky alcohol consumption. 

 

The approximately fourfold increased relative risk for completed suicide in subjects with smoking and risky alcohol consumption indicates a synergistic effect which deserves an increased alertness. 

 

 

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b.schneider@em.uni-frankfurt.de

Cognitive Performance in Treatment-Naïve Active Alcoholics

Most studies reporting cognitive deficits in chronic alcoholics have relied on treatment samples (predominantly men) from inpatient or outpatient treatment facilities. However, the majority of chronic alcoholics have never been in treatment and there is increasing evidence that treated and non-treatment-seeking alcoholic samples come from different populations with regard to alcohol use and other factors related to the severity of disease. 

Accordingly, in the present study, we assessed a broad range of cognitive functions in 55 treatment-naïve alcohol-dependent (TNAD) individuals and 55 nonalcoholic controls (NAC) matched for age and education. 

In addition, a goal of the present study was to assess potential differential effects of alcohol dependence on cognitive performance in TNAD men and women.

Comprehensive neuropsychological assessment was conducted on TNAD and NAC. The following 9 performance domains, each consisting of multiple measures, were examined: attention, auditory working memory, verbal processing, abstraction/cognitive flexibility, psychomotor function, immediate memory, delayed memory, reaction time, and spatial processing.

Analysis revealed no cognitive deficits in TNAD, relative to NAC, in any of the 9 cognitive domains. TNAD performed better than NAC in the attention domain. In addition, while men performed better than women in the spatial domain, there were no TNAD versus NAC group by gender interactions for any domain.

Our results extend findings that TNAD show minimal behavioral effects of chronic heavy alcohol use and are consistent with the contention that TNAD are relatively cognitively intact. 

Differences between our findings and those often reported for alcoholics recruited from treatment settings may be understood in terms of differences in alcohol use, along with genetic, psychiatric, and nutritional factors. 

In addition, the lack of differential effects of alcohol dependence on male and female cognitive performance in our study suggests that TNAD men and women do not differ in the severity of cerebral consequences of alcohol dependence.



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george@nbresearch.com

Acupuncture Inhibits GABA Neuron Activity in the Ventral Tegmental Area and Reduces Ethanol Self-Administration

Withdrawal from chronic ethanol enhances ventral tegmental area (VTA) GABA neuron excitability and reduces mesolimbic dopamine (DA) neurotransmission, which is suppressed by acupuncture at Shenmen (HT7) points (Zhao et al., 2006). 

The aim of this study was to evaluate the effects of HT7 acupuncture on VTA GABA neuron excitability, ethanol inhibition of VTA GABA neuron firing rate, and ethanol self-administration. A role for opioid receptors (ORs) in ethanol and acupuncture effects is also explored.

Using electrophysiological methods in mature rats, we evaluated the effects of HT7 stimulation and opioid antagonists on VTA GABA neuron firing rate. Using behavioral paradigms in rats, we evaluated the effects of HT7 stimulation and opioid antagonists on ethanol self-administration using a modification of the sucrose-fading procedure.

HT7 stimulation produced a biphasic modulation of VTA GABA neuron firing rate characterized by transient enhancement followed by inhibition and subsequent recovery in 5 minutes. HT7 inhibition of VTA GABA neuron firing rate was blocked by systemic administration of the nonselective μ-opioid receptor antagonist naloxone. 

HT7 stimulation significantly reduced ethanol suppression of VTA GABA neuron firing rate, which was also blocked by naloxone. HT7 acupuncture reduced ethanol self-administration without affecting sucrose consumption. 

Systemic administration of the δ-opioid receptor (DOR) antagonist naltrindole blocked ethanol suppression of VTA GABA neuron firing rate and significantly reduced ethanol self-administration without affecting sucrose consumption.

These findings suggest that DOR-mediated opioid modulation of VTA GABA neurons may mediate acupuncture’s role in modulating mesolimbic DA release and suppressing the reinforcing effects of ethanol.



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Request Reprint E-Mail: scott_steffensen@byu.edu    

Area of residence and alcohol-related mortality risk: a five-year follow-up study

To examine differences in alcohol-related mortality risk between areas, while adjusting for the characteristics of the individuals living within these areas.

A 5-year longitudinal study of individual and area characteristics of those dying and not dying from alcohol-related deaths.

The Northern Ireland Mortality study.

A total of 720 627 people aged 25–74, enumerated in the Northern Ireland 2001 Census, not living in communal establishments.

Five hundred and seventy-eight alcohol-related deaths.

There was an increased risk of alcohol-related mortality among disadvantaged individuals, and divorced, widowed and separated males. The risk of an alcohol-related death was significantly higher in deprived areas for both males [hazard ratio (HR) 3.70; 95% confidence interval (CI) 2.65, 5.18] and females (HR 2.67 (95% CI 1.72, 4.15); however, once adjustment was made for the characteristics of the individuals living within areas, the excess risk for more deprived areas disappeared. Both males and females in rural areas had a reduced risk of an alcohol-related death compared to their counterparts in urban areas; these differences remained after adjustment for the composition of the people within these areas.

 Alcohol-related mortality is higher in more deprived, compared to more affluent areas; however, this appears to be due to characteristics of individuals within deprived areas, rather than to some independent effect of area deprivation per se. Risk of alcohol-related mortality is lower in rural than urban areas, but the cause is unknown.


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sheelah.connolly@qub.ac.uk

Challenges in Developing Evidence-Based Recommendations Using the GRADE Approach: The Case of Mental, Neurological, and Substance Use Disorders

The World Health Organization (WHO) has been criticized recently for recommendations based on systematic reviews of the best available evidence and for the quality of some of its guidelines [1]–[3]. 

In 2007, WHO put in place procedures for developing transparent, evidence-based guidelines based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology [4],[5]. 

This methodology, developed by an international network of methodologists with an interest in grading quality of evidence and strength of recommendations (Box 1), has now been used to produce WHO guidelines for several topics. These include rapid advice guidelines for the pharmacological management of human H5N1 virus infection [6],[7] and guidelines on a single specific clinical topic such as psychosocially assisted pharmacological treatment of opioid dependence [8]. 

However, the GRADE approach has not yet been applied to develop recommendations that cover a broad range of conditions and interventions.

WHO is in the process of developing a model intervention guide within its mental health Gap Action Programme (mhGAP) [9]. The model intervention guide provides recommendations to facilitate care at first and second level facilities by the non-specialist health care providers in low- and middle-income countries (Box 2). These recommendations will be based on the GRADE approach. 

To our knowledge, this is the first exercise involving a systematic evaluation of evidence in this area. Other initiatives, for example the recently published reviews of evidence for packages of care for mental, neurological, and substance use disorders in low- and middle-income countries, did not use GRADE methodology [10]. 

This paper describes the use and adaptation of the GRADE approach in developing the guidelines for the mhGAP model intervention guide.

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