New drugs for addiction: focus on attenuating core behavioural components of heroin, cocaine and alcohol addiction

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Addiction to drugs such as heroin, cocaine and alcohol are a major problem in our society and globally. Is it possible to understand the processes that lead to addiction and to develop drugs that can be used for treatment? These are the two major questions that motivate the ICCAM addictions research cluster and this application. The ICCAM cluster brings together clinical and preclinical researchers from Imperial College London, Cambridge and Manchester Universities to address the problem of drug development for addiction. We seek to identify rational potential targets for drug development based upon our understanding of the pharmacology and brain processes engaged in addiction, rather than a random ?shotgun? approach. As a society, many think of addiction to drugs such as heroin, cocaine and alcohol as individual conditions with underlying social causes. This may not be the case with the established clinical condition, and this point of view may have impeded rational drug development for these disorders. The ICCAM cluster has identified multiple potential therapeutic drugs that may be of use in the treatment of addiction and now seeks to develop a ?platform? to rapidly assess their efficacy in humans. The word ?platform? means that we will adopt a common research approach based at each of our three sites to study the effects of particular drugs in human participants on processes that are relevant to addiction. We will use state of the art brain imaging techniques to study the effect of drugs on brain activity while a person responds to rewards, for example. These will be combined with neuropsychological assessment and monitoring of clinical outcomes to develop our research capacity.

Technical Summary

Substance Use Disorders are of large and growing prevalence and carry substantial morbidity, mortality and public costs, yet pharmacotherapy is at an early stage of development. While social context, public health policy and psychological approaches are clearly relevant to development and treatment of addiction they are of both limited efficacy and specificity, underlining the need for pharmacotherapy. Despite the proven utility of some drug interventions for addiction [eg methadone, buprenorphine, naltrexone for heroin dependence and acamprosate and naltrexone for alcohol dependence] many patients do not respond. There are no proven pharmacotherapies for cocaine. There is a pressing need to develop novel pharmacotherapies acting across a broader range of components of addictive processes. To this end, there have been major advances in recent years in the understanding of the neurobiology of addiction which offers a new approach to identifying drug targets based on brain mechanisms. Our cluster will use a new experimental medicine research ?platform? and work with new potential drug treatments provided in part by our industrial stakeholder GlaxoSmithKline [GSK]. This initial cluster application develops a platform to assess candidate brain systems underpinning relapse at molecular, network and behavioural levels by assessing three high-likelihood, theoretically critical, target mechanisms comprising: dopamine DRD3 receptors, for relapse prevention primarily by reducing cue-reactivity/craving and impulsivity; ?-opioid receptors, which mediate the reinforcing effects of opioids and are also implicated in impulsivity and hence relapse, especially under conditions of stress; and NK1 receptors, implicated in both stress and reward responses. These drugs will be assessed with novel psychological and fMRI paradigms in human alcohol, heroin and cocaine addicts and in parallel preclinical studies. The platform will then be available for the study of other candidate treatment approaches for addiction that may include for example orexin antagonists and appetite regulating peptides.

Publications

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Caprioli D (2015) Dissociable rate-dependent effects of oral methylphenidate on impulsivity and D2/3 receptor availability in the striatum. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Colasanti A (2011) Opioids and anxiety. in Journal of psychopharmacology (Oxford, England)

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Hayes DJ (2014) Brain ?-aminobutyric acid: a neglected role in impulsivity. in The European journal of neuroscience

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Mitchell F (2017) Anne Lingford-Hughes: to get into addiction, just say yes. in The lancet. Psychiatry

 
Description Heptares Therapeutics Ltd
Amount £528,093 (GBP)
Organisation P1vital Consortium 
Sector Private
Country United Kingdom
Start  
End 03/2017
 
Description ICCAM cluster (Cambridge site)
Amount £413,162 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2011 
End 07/2013
 
Title addiction brain provocation tests 
Description 3 fmri exposure paradigms to probe stress impulsivity and rewards sensitivity developed and validated 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact useful platform technology 
 
Description link with GSK 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution this is a shared project with the PET analaysi team at GSK Uk in the clinical imaging centre
Collaborator Contribution help in data acquisition and analysis
Impact several abstract presentations at intrnational PET meetings
Start Year 2009
 
Description Disseminating information about the MARC scheme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presented MARC scheme, its aims and opportunities. Presented at RCPsych Addictions Faculty Meeting 2016 as well as other regional meetings alongside presentation of research outputs from other grants
Year(s) Of Engagement Activity 2015,2016
URL http://www.imperial.ac.uk/medicine/mrc-addiction-research-clinical-training/
 
Description MRC Summer school, Cardiff Neuroscience 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Speaker at MRC Centre for Neuropsychiatric Genetics and Genomics Summer School in Brain Disorder Research: https://www.cardiff.ac.uk/medicine/news/remedy/27/mrc-cngg-summer-school
Cover neurobiology of addiction and its treatment. Promote MARC scheme to delegates.
Year(s) Of Engagement Activity 2015,2017,2018