A Blocker of N- and T-type Voltage-Gated Calcium Channels Attenuates Ethanol-Induced Intoxication, Place Preference, Self-Administration, and Reinstatement
The Journal of Neuroscience, November 5, 2008, 28(45):11712-11719


There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems.

We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication. NP078585 also attenuated the reinforcing and rewarding properties of ethanol, measured by operant self-administration and the expression of an ethanol conditioned place preference, and abolished stress-induced reinstatement of ethanol seeking. NP078585 did not affect alcohol responses in mice lacking N-type calcium channels.

These results suggest that selective calcium channel inhibitors may be useful in reducing acute ethanol intoxication and alcohol consumption by human alcoholics.

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Market Report - Pipeline Insight - Substance Dependence - Part II - Alcohol

The continued uptake of existing brands and the launch of two opioid antagonists will cause the market to grow at a compound annual growth rate of 13.5% from 2006 to reach $304m across the seven major markets by 2016. The alcohol dependence market requires a paradigm shift away from the public perception that it is a behavioral disorder towards being regarded as a treatable medical condition.

Scope

Analysis of epidemiology, unmet needs and clinical trial design in alcohol dependence with insight from key opinion leaders

Overview of the current alcohol dependence market.

Analysis of patient potential, marketing factors, commercial attractiveness and clinical attractiveness of key late-stage pipeline drugs.

Indication-specific forecasts of key drug key late-stage pipeline drugs revenues to 2016.

Highlights

The current alcohol dependence pipeline is small in comparison to other central nervous system markets. Opioid antagonists are the most prevalent drug class in late-stage development and include two reformulations of naltrexone. It is believed that the current alcohol dependence pipeline to be weak and lacking in innovation.

The efficacy of currently marketed pharmaceutical products is limited, thereby leaving market opportunity for new therapies. Furthermore, in view of the poor medication compliance rate in alcohol dependent patients, pipeline drugs that possess the potential to improve patient compliance can expect to receive a strong uptake.

Companies developing naltrexone depot drugs will experience difficulty distinguishing their products from Vivitrol (naltrexone once-monthly controlled-release, Alkermes/Cephalon) unless they price their drugs competitively and/or incorporate an injection device that produces less pain and fewer injection site reactions.
. . . . .

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Hundreds of children under 10 hospitalised with alcohol problems

Times Online November 9, 2008
Kaya Burgess

A child under ten is admitted to hospital to be treated for alcohol-related problems once every three days in England, according to Government figures revealed today.

Between 2002 and 2007, a total of 648 under-tens and more than 24,000 under-16s were hospitalised because of excessive intake of alcohol.

The figures come from within a parliamentary answer revealed by the Liberal Democrats ahead of the launch tomorrow of their strategy to tackle underage and binge drinking.

In the 16-17 age bracket alone, they revealed, around 12,500 teenagers were admitted to Accident and Emergency for alcohol-related conditions, marking an increase of 95 per cent between 2002 and 2007.

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Interventions might offer a pregnant pause in addiction
Nature Medicine 14, 1168 (2008)

Doctors have known for decades that cigarettes and alcohol harm developing babies. Now, because many pregnant women find it difficult to beat these addictions, research has begun looking for ways to minimize their damage to the fetus.

. . . . .

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Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior
Psychopharmacology Online First 6 November 2008

The sensitivity to ethanol central effects is partially determined by the subunit composition of brain nicotinic acetylcholine receptors (nAChRs).

Thus, the effects of intraventral tegmental area (VTA) administration of the nicotinic subunit-specific antagonist, α-conotoxin MII (αCtxMII, α₃β₂*, β₃*, α₆*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-β-erythroidine (DHβE, α₄β₂*), and methyllycaconitine (MLA, α₇*) to elucidate involvement of different subunits of nAChRs in operant ethanol self-administration and relapse-like activation of ethanol consumption after ethanol deprivation in rats.

αCtxMII reduced operant ethanol self-administration and blocked the deprivation-induced relapse-like ethanol consumption. MEC reduced operant ethanol self-administration and inhibited the deprivation-induced increase in alcohol consumption. DHβE did not alter ethanol self-administration in the lower-dose range but inhibited ethanol intake at a higher dose (4 mg/kg), although this effect might have been nonspecific. MLA failed to block self-administration of ethanol and relapse-like drinking after deprivation.

Our results indicate that nAChRs are involved in the modulation of operant alcohol self-administration and relapse-like alcohol drinking behavior in rats. Our observations support the working hypothesis that systemically active selective ligands for nAChR α₃β₂*, β₃, and/or α₆* receptor subunits might be of therapeutic value for the treatment of alcoholism.

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Request Reprint E-Mail: Sture.Liljequist@ki.se
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Family History of Alcohol Dependence and Initial Antidepressant Response to an N-methyl-D-aspartate Antagonist
Biological Psychiatry Article in Press 8 November 2008

A high rate of comorbidity exists between mood disorders and alcohol dependence. Furthermore, both ketamine, a dissociative anesthetic with a recently described rapid-onset antidepressant effect, and ethanol are N-methyl-D-aspartate (NMDA) receptor antagonists. Previous investigations of healthy individuals with a family history of alcohol dependence have found that these individuals have an attenuated response to ketamine's perceptual disturbance and dysphoric effects similar to that found in individuals with a self-reported history of alcohol dependence.

This study investigated whether a family history of alcohol dependence influences ketamine's initial antidepressant effect.

Twenty-six subjects with DSM-IV treatment-resistant major depression were given an open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg) and rated using various depression scales at baseline, 40, 80, 120, and 230 min postinfusion. The primary outcome measure was Montgomery-Asberg Depression Rating Scale (MADRS) scores

Subjects with a family history of alcohol dependence showed significantly greater improvement in MADRS scores compared with subjects who had no family history of alcohol dependence.

A family history of alcohol dependence appears to predict a rapid initial antidepressant response to an NMDA receptor antagonist.

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Request Reprint E-Mail: zaratec@mail.nih.gov

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Disruption of Orbitofrontal Cortex Laterality in Offspring from Multiplex Alcohol Dependence Families
Biological Psychiatry Article in Press, 4 november 2008

Increased susceptibility for developing alcohol dependence (AD) might be related to structural differences in brain circuits that influence the salience of rewards and/or modify the efficiency of information processing. The role of the orbitofrontal cortex (OFC) in regulating emotional processing is increasingly being recognized along with its association with impulsive behavior.

High-risk offspring from multiplex for AD families showed decreased right/left OFC volumes in comparison with control subjects. Smaller volume in the right hemisphere was significantly associated with variation in the 5-HTT and BDNF genes. White matter (WM) ratios showed a positive correlation with MPQ Control scale scores, indicating that reduced OFC WM is related to greater impulsivity.

Offspring from multiplex families for AD manifest genetic susceptibility by exhibiting disruption in the laterality of the OFC volume that is related to greater impulsivity (lower Control scale scores). This disruption in OFC laterality is related to variation in genes associated with neuronal growth.

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Request Reprint E-Mail: syh50@imap.pitt.edu

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Induction of brain CYP2E1 changes the effects of ethanol on dopamine release in nucleus accumbens shell
Drug and Alcohol Dependence Article in Press, 6 November 2008


CYP2E1 is an important enzyme involved in the brain metabolism of ethanol that can be induced by chronic consumption of alcohol. Recent works have highlighted the importance of this system in the context of the behavioural effects of ethanol. Unfortunately, the underlying neurochemical events for these behavioural changes, has not been yet explored.

In this work, we have started this exploration by analyzing the possible changes in the neurochemical response of the mesolimbic system to ethanol after pharmacological induction of brain CYP2E1.

We have used the dopamine extracellular levels in nucleus accumbens (NAc) core and shell, measured by means of microdialysis in vivo, as an index of the effects of ethanol. Acetone 1% in the tap water was used to induce brain CYP2E1. Efficacy of the induction protocol was assessed by immunoblotting.

Intravenous administration of 1.5 g/kg of ethanol in control rats provoked a significant increase of the dopamine levels in both the core (up to 127% of baseline) and the shell (up to 122% of baseline) of the NAc. However, the same dose of ethanol in acetone-treated rats only increased the dopamine extracellular levels in the core (up to 142% of baseline) whereas dopamine levels in the shell subregion remain unaltered relative to baseline.

The results of this study indicate that induction of CYP2E1 changes the response of the mesolimbic system to ethanol in a region-dependent manner. Two hypotheses are postulated to explain the observed effects.

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Request Reprint E-Mail: lfgran@uv.es
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N²-Ethyldeoxyguanosine as a Potential Biomarker for Assessing Effects of Alcohol Consumption on DNA
Cancer Epidemiology Biomarkers & Prevention 17, 3026-3032, November 1, 2008


Head and neck cancers are causally related to alcohol consumption, but the underlying mechanisms are unclear. Ethanol is metabolized to acetaldehyde, an experimental carcinogen. Quantitation of the major DNA adduct of acetaldehyde, N²-ethylidenedeoxyguanosine, in human tissues could help to elucidate the mechanism of alcohol carcinogenicity.

We applied a quantitative method for the analysis of this adduct, measured as the NaBH₃CN reduction product N²-ethyldeoxyguanosine (N²-ethyl-dGuo) by liquid chromatography-electrospray ionization-tandem mass spectrometry-selected reaction monitoring, on DNA (0.04 ± 0.03 mg) isolated from blood collected from control subjects recruited from two studies conducted in different areas of Europe between 1999 and 2005. The group selected from the first study (n = 127) included alcohol drinkers and abstainers while the group from the second study (n = 50) included only heavy drinkers. N²-ethyl-dGuo was detected in all DNA samples.

After adjusting for potential confounders, in the first study, drinkers showed a higher level of N²-ethyl-dGuo (5,270 ± 8,770 fmol/µmol dGuo) compared with nondrinkers (2,690 ± 3040 fmol/µmol dGuo; P = 0.04). A significant trend according to dose was observed in both studies (P = 0.02 and 0.04, respectively). Taking into account the amount of alcohol consumption, adduct levels were higher in younger compared with older subjects (P = 0.01), whereas no differences were observed comparing men with women.

These results show the feasibility of quantifying N²-ethyl-dGuo in small-volume blood samples and are consistent with the hypothesis that ethanol contributes to carcinogenesis through DNA adducts formation.

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Request Reprint E-Mail: boffetta@iarc.fr
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Multiple indicator hidden Markov model with an application to medical utilization data
Statistics in Medicine Published Online: 7 Nov 2008

Monthly counts of medical visits across several years for persons identified to have alcoholism problems are modeled using two-state hidden Markov models (HMM) in order to describe the effect of alcoholism treatment on the likelihood of persons to be in a healthy or unhealthy state.

The medical visits can be classified into different types leading to multivariate counts of medical visits each month. A multiple indicator HMM is introduced, which simultaneously fits the multivariate Poisson counts by assuming a shared hidden state underlying all of them. The multiple indicator HMM borrows information across different types of medical encounters. A univariate HMM based on the total count across types of medical visits each month is also considered.
Comparisons between the multiple indicator HMM and the total count HMM are made, as well as comparisons with more traditional longitudinal models that directly model the counts.

A Bayesian framework is used for the estimation of the HMM and implementation is in Winbugs

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Request Reprint E-Mail: melanie@biostat.umn.edu
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Commission on Social Determinants of Health - Final Report

Closing the gap in a generation: Health equity through action on the social determinants of health

Social justice is a matter of life and death. It affects the way people live, their consequent chance of illness, and their risk of premature death. We watch in wonder as life expectancy and good health continue to increase in parts of the world and in alarm as they fail to improve in others.

pg. 135
There are nearly 2 million alcohol-related deaths per year, of the same order as HIV/AIDS at 2.9 million. Absolute levels of alcohol-related disease and disability are as high in the poorest countries of Africa and America as in Western Europe and North America. Alcohol-related disease is highest in the former Soviet Union and Central Asia, amounting to 13% of the total burden. In the Russian Federation itself it is even higher (PPHCKN, 2007b). A society without effective alcohol policies is likely to experience a sharp rise in alcohol problems during economic development. The transition in the former Soviet Union is a striking example. In the Russian Federation, the ‘shock therapy’ and economic liberalization in 1992 included a total deregulation of trade in alcoholic beverages. The subsequent mortality rise in the Russian Federation has been linked to a rise in binge drinking of alcohol (Leon et al., 1997;
PPHCKN, 2007b).

pg. 142
Learning from the FCTC, the Commission urges WHO to initiate a discussion with Member States on regulatory action for alcohol control (Boxes 12.18 and 12.19). The WHO European Region suffers the highest levels of alcoho lrelated disease and violence, with very large differences in alcohol-related mortality between countries. European policy discussion has been characterized by a conflict of view: is alcohol a commodity like any other, or should it be seen as a public health concern, whose trade could be regulated to protect people’s health? The Commission urges governments in the WHO European Region and globally to work together to limit alcohol-related harm

Executive summary (PDF)

Download the full report (PDF)
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Editorials - International regulation of alcohol
BMJ 2008;337:a2364

A framework convention is needed, as for tobacco control

The World Health Organization’s Commission on Social Determinants of Health has just issued its main report,¹ which lays out an ambitious programme of actions to tackle health inequity. The commission notes the substantial contribution of alcohol to injury, disease, and death worldwide,² and it proposes that WHO and member nations should use the 2005 framework convention on tobacco control as a model for alcohol control. We agree that it is time to adopt such a framework. The commission’s work underscores the urgent need for international agreements that promote alcohol controls throughout the developing and developed world. Increasing affluence in the fastest developing regions of the world—East Asia, the Pacific region, and South Asia—has led to increased alcohol consumption, along with a higher burden of harm caused by alcohol. These increases foreshadow future trends in consumption and harm for other developing countries—such as those in Africa, Central America, and South America
. . . . .

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Request Reprint E-Mail: RobinR@turningpoint.org.au
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Alcohol Taxes and Fees: An economic and historical perspective

Testimony from Bruce Lee Livingston, MPP
Executive Director, Marin Institute
Assembly Select Committee on Alcohol and Drug Abuse
Thursday, March 6, 2008

I am going to give a brief history of alcohol tax and fee proposals, compare California’s tax rates to other states, present alcohol cost and harm data, and then run through a few tax and fee options that could generate hundreds of millions, if not billions, of dollar.
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Read Full Testimony (PDF)
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Press Release - Nickel a Drink to Save State Budgets

Marin Institute Calls on States with Budget Shortfalls to Follow California in Proposing an Alcohol Tax Increase

Long Overdue Tax Increases Could Ease Budget Deficits in 39 States and Mitigate Alcohol-Related Costs

SAN RAFAEL, CA (November 7, 2008) – Public health advocates are calling on policymakers around the nation to follow the lead of California Governor Arnold Schwarzenegger to help fund ailing state budgets through higher alcohol taxes. On Thursday, Governor Schwarzenegger proposed a nickel a drink tax increase on beer, wine, and distilled spirits to help reduce California’s budget shortfall, while providing critical support to the state’s programs that reduce alcohol-related problems.

At least 38 other states also face serious budget deficits, totaling more than $60 billion dollars, according to the Center on Budget and Policy Priorities. “A nickel a drink -- It’s the change we need to fix budgets around the nation,” said Bruce Lee Livingston, executive director of Marin Institute, the California-based alcohol industry watchdog. “The largest states, such as New York and Florida can avoid cutting essential programs through long-overdue alcohol tax increases,” Livingston added. California’s proposal accomplishes exactly that.
. . . . . .

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Governor Schwarzenegger Proposes an Alcohol Tax Increase

California Governor Schwarzenegger has proposed a nickel a drink alcohol tax increase on wine, beer and distilled spirits to take effect January 1, 2009. The long overdue tax increase will raise new funds – estimated at over $878 million over the next year and a half - to help reduce the state’s serious budget shortfall while providing critical support to programs that deal specifically with alcohol-related problems.

SEE BUDGET PROPOSAL see pg. 12

The last alcohol tax increase in California was in 1992, and was only a penny on a glass of wine and two cents per can of beer and shot of spirits. Since that time, rising inflation has led to a 49% net decrease in state alcohol taxes. At the same time, alcohol-related problems have increased dramatically and now cost the state and its citizens $38 billions dollars annually in healthcare, criminal justice, addiction treatment, lost productivity and myriad other costs.

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Press Release - Governor Schwarzenegger Announces Plan to Address Budget Emergency, Stimulate California’s Economy
11/06/20

To remedy California's urgent budget situation due to economic conditions radically deteriorating since the 2008 Budget Act was signed, Governor Arnold Schwarzenegger today called a special session of the legislature and announced an action plan to get our budget back on track, invigorate our economy and generate jobs for the state's unemployed. The Governor called for a combination of cuts and revenue increases to solve California's budget shortfall which has now reached $11.2 billion. The actions prescribed by the Governor must be taken up as quickly as possible in order to prevent a cash crisis that will jeopardize vital state services.

. . . . .Additionally, the Governor called for additional revenue increases including broadening the sales and use tax to include certain services, imposing an oil severance tax upon any oil producer that extracts oil from the earth or water in this state and increasing the alcohol excise tax by five cents a drink.

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Recollective experience in alcohol dependence: a laboratory study
Addiction Volume 103 Issue 12, Pages 1969 - 1978


Alcohol dependence has been linked to dysfunction of fronto-temporo-striatal circuits which mediate memory and executive function. The present study aimed to explore the specificity of recognition memory changes in alcohol dependence.

Alcohol-dependent patients showed intact hit rates, but increased false alarm rates and an impaired ability to remember the learning context. Both the DPSD model and PDP estimates yielded significantly reduced recollection estimates in the alcohol-dependent compared to control subjects. Whether or not familiarity was impaired, depended upon the sensitivity of the estimation procedure.

Taken together, the result pattern suggests a significant impairment in recollection and mild familiarity changes in recently detoxified, predominantly male, alcohol-dependent subjects.

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Request Reprint E-Mail: patrizia.thoma@rub.de

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Alcohol consumption and mortality and hospital admissions in men from the Midspan Collaborative cohort study
Addiction Volume 103 Issue 12, Pages 1979 - 1986


To investigate the relationships between alcohol consumption and mortality and morbidity risk by specific causes.

Mortality risk was increased for men drinking 15–21 or more units per week for all causes, stroke, liver disease and alcohol-related causes. For respiratory mortality, drinkers of 35 or more units had double the risk compared to non-drinkers. CHD mortality showed increasing trends with consumption when adjusted for age and after full adjustment showed no clear patterns, although the 8–14 units group had a lower risk than non-drinkers [relative rate 0.81 (0.68–0.97)]. Hospital admissions had similar patterns to mortality for stroke and liver disease. Increased risk began at 8–14 units for alcohol-related admissions, and at 15–21 units for respiratory admissions. Non-drinkers had higher risks of having a CHD admission than drinkers and there were decreasing trends with increasing consumption (P = 0.019).

Consumption of 15–21 units per week and over was associated with increased mortality from most causes and increased risk of hospital admissions from stroke, liver disease and respiratory diseases. Alcohol-related admissions were raised from 8 to 14 units. Alcohol use may have been under-reported in our study, but it was similar to other studies of the time. The apparent protective effect of alcohol with CHD admissions could be due partly to detrimental effects of heavy drinking causing sudden deaths. The associations, including that with respiratory disease, may arise from inadequate adjustment for confounding by other factors such as smoking.

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Request Reprint E-Mail: c.l.hart@udcf.gla.ac.uk
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Recovery Capital: A Primer for Addiction Professionals

Written by William L. White, MA and William Cloud, PhD

Thursday, 06 November 2008 The history of addiction treatment in America contains within it a history of key ideas that have transformed service philosophies and practices. In the early history of modern treatment, for example, chemical dependency emerged as a core idea that helped integrate what were then two separate fields: one focused on alcoholism; the other on drug addiction. Other concepts, such as codependency, dual diagnosis, gender-specific, developmental appropriateness, cultural competence, trauma-informed, evidence-based, stages of change, motivational enhancement, recovery management and recovery coaching helped, or are now helping, transform addiction treatment into a more person-centered, holistic, family-centered and recovery-focused system of care. Addiction professionals across America are witnessing the field’s paradigmatic shift from a pathology and intervention focus to a recovery focus (White, 2004; 2005). Attention on the lived solution to alcohol and other drug (AOD) problems is reflected in the growing interest in defining recovery; conducting recovery prevalence surveys; illuminating the varieties of recovery experiences; and mapping the patterns, processes, and stages of long-term recovery (Betty Ford Institute Consensus Panel, 2007; White & Kurtz, 2006). One of the key ideas at the core of this shift is that of recovery capital (RC). This article defines RC and explores how attention to RC can be integrated into the service practices of front-line addiction professionals. . . . . . . Read Full Article ________________________________________________

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Influences of Gender and Age on Relationships Between Alcohol Drinking and Atherosclerotic Risk Factors
Alcoholism: Clinical and Experimental Research Published Online: 5 Nov 2008


Alcohol drinking affects atherosclerotic progression mainly through blood pressure and lipid metabolism. The purpose of the present study was to clarify whether effects of alcohol drinking on atherosclerotic risk factors differ by gender and age.

The mean level of body mass index (BMI) was slightly but significantly lower in drinkers than in nondrinkers in the thirties, forties, and fifties age groups in men and in the twenties, thirties, forties, and fifties age groups in women, while this tendency was not found in the sixties age groups of men and women. In men, mean blood pressure was higher in moderate-to-heavy drinkers than in nondrinkers in all age groups and was higher in light drinkers than in nondrinkers only in the age groups after 40 years. Mean blood pressure of women was higher in the moderate-to-heavy drinker group than in the nondrinker group and this difference became higher with advance of age. In women, mean blood pressure was not affected by light drinking in any of the age groups except for the fifties age group. In men, serum total cholesterol was higher in drinkers than in nondrinkers in the twenties age group but was lower in drinkers than in nondrinkers at thirties or older. Serum total cholesterol in women was lower in drinkers than in nondrinkers in the age groups from twenties to forties but tended to be higher in drinkers than in nondrinkers in the sixties age group. Serum HDL cholesterol increased with advance of age from thirties to sixties in men, while it decreased with advance of age from twenties to sixties in women. Serum HDL cholesterol was higher in drinkers than in nondrinkers in all age groups of men and women, and atherogenic index, calculated by using serum total cholesterol and HDL cholesterol concentrations, was lower in drinkers than in nondrinkers in all age groups of men and women.

Both in men and women, blood pressure and HDL cholesterol were strongly affected by alcohol drinking: the elevating effect of alcohol drinking on blood pressure was more prominent in the elderly than in the young, while the elevating effect of alcohol drinking on serum HDL cholesterol was not influenced by age. Relationships of drinking with total cholesterol and BMI vary by age and gender.

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Request Reprint E-Mail: wakabaya@hyo-med.ac.jp

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