Sensitisation to alcohol withdrawal: consequences and mechanisms

Lead Research Organisation: University of Sussex
Department Name: Brighton and Sussex Medical School

Abstract

Among those treated for alcoholism, a typical pattern consists of a period of problem drinking, treatment involving detoxification, a period of abstinence, which may be very short, followed by relapse. Such cycles are often repeated many times during an alcoholic career, each withdrawal episode increasing intensity of withdrawal and risk of seizures. Patterns of binge drinking by young adults, involving bouts of intoxication and withdrawal possess some features similar to repeated withdrawal. We have found that such individuals show impairments in cognitive and emotional competence, and we have been able to reproduce similar effects in rodents, in which we have begun to study the brain changes responsible for the deficits. The current project, to be undertaken by clinical and experimental scientists at the University of Sussex, and the Institute of Psychiatry, will extend this work to understand better the brain areas, and neuronal processes impaired by repeated withdrawal from alcohol. Using brain imaging and psychological testing of people who abuse alcohol, we will investigate whether repeated alcohol withdrawal, and binge drinking, compromise function of the frontal areas of the brain that are involved in judgement and control of behaviour, and which are likely to be important in controlling urges to drink, and of the brain area called the amygdala that is involved in emotions. Because it is difficult to discover whether differences observed between normal people and those who abuse alcohol are the cause of alcohol abuse, or its effect, related studies will be carried out in rats to determine whether repeated alcohol withdrawal causes related effects. Ultimately we would hope to be able to prevent brain changes that occur in withdrawal, and help alcoholics control their drinking more easily.

Technical Summary

One of the major health concerns associated with alcoholism is brought about by repeated cycles of problem drinking, followed by detoxification, a period of abstinence, and finally relapse. Such cycles may be repeated many times during an alcoholic career, each successive withdrawal episode being associated with increased risk of seizures. We have shown that patients who have undergone repeated episodes of withdrawal also show altered affect, and deterioration of cognitive abilities when compared to patients with fewer withdrawals, and we have found related impairments in young binge drinkers. As well as being deleterious in their own right, such changes may also contribute to future drug taking behaviour, whilst related impairments in young binge drinkers may indicate a vulnerability to develop alcoholism. The proposed research will test our working hypothesis that many of the cognitive and emotional impairments observed following repeated experience of withdrawal are attributable to altered function of a system including prefrontal cortex and amygdala. In human alcoholics and binge drinkers neuropsychological tests sensitive to alterations in the brain areas concerned, combined with functional imaging, will be used to study changes in brain activation during the performance of these tasks.
More detailed neuronal circuitry and underlying neurobiological mechanisms will be examined in parallel behavioural studies in rats and genetically manipulated mice. In animal studies the development and progression of withdrawal-kindling, following more severe withdrawal or a greater number of withdrawal cycles, will be studied using behavioural paradigms targeted at different brain regions postulated from imaging studies to be important in mediating the effects of repeated withdrawal. Chemical inactivation of these regions during withdrawal, followed by investigations of the subsequent effect on withdrawal-sensitive behavioural paradigms will then be used to study the functional importance of these regions during withdrawal. Finally, using pharmacological tools and transgenic mouse models, GABAergic and glutamatergic processes known to be involved in synaptic plasticity, and which seem likely to contribute to the synaptic sensitisation thought to underlie repeated withdrawal effects, will be studied. The ultimate aim of the project is to identify potential targets for drug treatments to prevent the consequences of repeated withdrawal in the alcoholic population.

Publications

10 25 50

 
Description AERC
Amount £21,000 (GBP)
Organisation Alcohol Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2010 
End 12/2012
 
Description BBSRC CASE Studentship (Johnson and Johnson)
Amount £74,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2009 
End 12/2012
 
Description BBSRC CASE Studentship (Pfizer)
Amount £70,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2006 
End 10/2010
 
Description DFG, Travellining Fellowship for Dr Sabine Loeber
Amount £50,000 (GBP)
Organisation German Research Foundation 
Sector Public
Country Germany
Start 01/2008 
End 06/2009
 
Description ESRC, PhD Studentship
Amount £80,000 (GBP)
Organisation Economic and Social Research Council 
Sector Public
Country United Kingdom
Start 10/2009 
End 09/2013
 
Description EU InterReg
Amount £357,435 (GBP)
Organisation European Commission 
Department European Regional Development Fund (ERDF)
Sector Public
Country European Union (EU)
Start 03/2009 
End 12/2012
 
Description European Research Advisory Board (ERAB) Project Grant
Amount £26,700 (GBP)
Organisation European Commission 
Department European Research Advisory Board (ERAB)
Sector Public
Country European Union (EU)
Start 01/2009 
End 12/2010
 
Description GSK
Amount £45,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 01/2011 
End 11/2011
 
Description AlcoBinge 
Organisation European Commission
Department European Regional Development Fund (ERDF)
Country European Union (EU) 
Sector Public 
PI Contribution This is a cross-regional collaboration between the Universities of Sussex, Rouen and Amiens. The University of Sussex will study the consequences of binge drinking on impulsivity using a mouse model and human fMRI methods following on from the MRC grant
Collaborator Contribution Availability of techniques not available at Sussex. Appointment of RA in Amiens to work on the project at SussexAvailability of techniques not available at Sussex
Impact Multidisciplinary - molecular biology, behavioural neuroscience, brain imaging
Start Year 2010
 
Description AlcoBinge 
Organisation University of Picardie Jules Verne
Department Department of Neurobiology
Country France 
Sector Academic/University 
PI Contribution This is a cross-regional collaboration between the Universities of Sussex, Rouen and Amiens. The University of Sussex will study the consequences of binge drinking on impulsivity using a mouse model and human fMRI methods following on from the MRC grant
Collaborator Contribution Availability of techniques not available at Sussex. Appointment of RA in Amiens to work on the project at SussexAvailability of techniques not available at Sussex
Impact Multidisciplinary - molecular biology, behavioural neuroscience, brain imaging
Start Year 2010
 
Description AlcoBinge 
Organisation University of Rouen
Department Department of Neurobiology
Country France 
Sector Academic/University 
PI Contribution This is a cross-regional collaboration between the Universities of Sussex, Rouen and Amiens. The University of Sussex will study the consequences of binge drinking on impulsivity using a mouse model and human fMRI methods following on from the MRC grant
Collaborator Contribution Availability of techniques not available at Sussex. Appointment of RA in Amiens to work on the project at SussexAvailability of techniques not available at Sussex
Impact Multidisciplinary - molecular biology, behavioural neuroscience, brain imaging
Start Year 2010
 
Description Collaboration with Pfizer 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution development of methods for studying effects of chronic ethanol and potential drugs of abuse on rodent measures of impulsivity
Collaborator Contribution Hosting student during CASE award
Impact method developed and transferred to Pfizer labs
Start Year 2006
 
Description GSK 
Organisation GlaxoSmithKline (GSK)
Department Psychiatry (GSK)
Country United Kingdom 
Sector Private 
PI Contribution Testing in mice of a novel agent for its potential utility in reducing alcohol intake
Collaborator Contribution Provsion of novel agent form testing utility as a treatment of alcohol abuse
Impact No outputs to date Collaboration is in mouse behaviour
Start Year 2011
 
Description central institute for mental health, mannheim 
Organisation Central Institute for Mental Health
Country Germany 
Sector Hospitals 
PI Contribution Hosted postdoctoral researcher and supervised her research
Collaborator Contribution Research collaboration. Partner contributed person and analysis expertise. See publications.
Impact see publications, first author Loeber 19922568 19487491 19468716
Start Year 2008
 
Description BBC Television Horizon Prpgramme td 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Participation in Horizon programme "Britain's most dangerous drug". Presentation on effects of binge drinking on brain function

Further doscussion at Dana Centre. see http.www.danacentre.org.uk/events/2008/02/05/360
Year(s) Of Engagement Activity 2008
URL http://www.danacentre.org.uk/events/2008/02/05/360
 
Description BBC radio interview ds 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Participation in BBC Radio 4 broadcast on Chemistry of Addiction (over two weeks)

none
Year(s) Of Engagement Activity 2007
 
Description British Association Festival of Science td 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Presentation on alcohol, binge drinking and brain function

extensive press coverage
Year(s) Of Engagement Activity 2008
 
Description Royal Society ds 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Invited lecture to International meeting of Addiction workers. Audience consisted of addiction scientists, professionals, policy makers, and press

None
Year(s) Of Engagement Activity 2007