Genetic influences underlying impulsivity and risk for drug addiction

Lead Research Organisation: University of Cambridge
Department Name: Psychology

Abstract

Despite intensive research efforts we still do not understand why some people use or become dependent on drugs such as crack cocaine nor do we have effective treatments to prevent or ameliorate this widespread and debilitating brain disorder. An important clue to the cause of drug addiction is that it tends to be associated with people who are naturally impulsive or who enjoy taking risks, as well as people diagnosed with certain childhood brain disorders such as attention deficit hyperactivity disorder (ADHD). Such traits and disorders appear to play an important role in determining the likelihood of future problem drug use by influencing the various stages of the pathway to addiction, including the chances of first coming into contact with drugs, the transition from occasional to regular drug use and the propensity for repeated episodes of drug binging and withdrawal. This research investigates the biological basis of such traits using a sophisticated gene hunting technique to determine the hereditary risk for drug addiction in close family members. Our research will be conducted using a colony of impulsive rats which carry a strongly increased risk for developing a drug taking habit. We will search over 10,000 known gene variations across the entire rat genetic code to pinpoint genes that underlie the impulsive trait. In so doing, we will provide a much fuller understanding of the genetic basis of risk for drug addiction, not only in our rat model but also in humans. This research will facilitate the discovery of new brain mechanisms and therapies to treat drug abuse and addiction as well as ADHD and related brain disorders.

Technical Summary

Drug addiction is a devastating brain disorder that wrecks the lives of individuals, families and the wider community with serious and growing repercussions for public health and crime rate in the UK. Although the precise cause of dug addiction is unknown it is widely hypothesised to be influenced by complex genetic and environmental factors that interact with direct drug-induced effects to affect the final pathway to addiction. Indeed, genetic influences are postulated to account for a substantial proportion of vulnerability to drug abuse and addiction, especially those that underlie complex personality traits such as impulsivity and risk taking and brain disorders frequently co-morbid with drug addiction, including attention deficit hyperactivity disorder (ADHD) and conduct disorder. This pilot study focuses on a spontaneously occurring form of impulsivity in rats that not only predisposes to excessive cocaine intake and the development of compulsive cocaine seeking it is also a marker for vulnerability to relapse. We aim to investigate the genetic basis of impulsivity by carrying out a genome-wide linkage analysis across 10,000 SNPs using a large sample of selectively inbred, multi-generational, impulsive rats. Genome-wide linkage analysis for impulsivity phenotypes (i.e., high versus low impulsivity) will be carried out using selected animals from three successive generations of inbreeding (in total n=250) for which a substantial heritable genetic variation has been determined. We will also investigate the influence of early environmental factors on impulsivity by cross-fostering rat offspring with dams of the opposite extreme phenotype (i.e., low impulsive pups reared by high impulsive dams and visa versa), thus addressing directly the contribution of genetic versus environmental determinants of vulnerability to drug addiction. This pilot study benefits from an already existing archive of tissue harvested from this multi-generation pedigree and the formation of a strategic new partnership between the MRC and Wellcome Trust funded Behavioural and Clinical Neuroscience Institute at Cambridge University and Tim Aitman?s genomics laboratory at the MRC Clinical Sciences Centre at Imperial College. The outcome of this pilot study will be the demonstration of linkage to discrete chromosomal regions that habour genetic determinants of impulsivity and related phenotypes and the identification of genes and pathways underlying heritable risk for drug abuse and addiction. This proof-of-principle study is especially important because it will enable comparative genetic analysis of strong translational relevance for human drug addiction and thereby identify potential new targets and therapies to promote abstinence and reduce the propensity to relapse.

Publications

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Barlow RL (2015) Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Barnes SA (2014) Impaired limbic cortico-striatal structure and sustained visual attention in a rodent model of schizophrenia. in The international journal of neuropsychopharmacology

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Dalley JW (2012) Dopamine, serotonin and impulsivity. in Neuroscience

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Dalley JW (2019) Shining the spotlight on the dark side of impulsivity. in Neuroscience and biobehavioral reviews

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Dalley JW (2017) Fractionating impulsivity: neuropsychiatric implications. in Nature reviews. Neuroscience

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Economidou D (2012) Norepinephrine and dopamine modulate impulsivity on the five-choice serial reaction time task through opponent actions in the shell and core sub-regions of the nucleus accumbens. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Everitt BJ (2016) Drug Addiction: Updating Actions to Habits to Compulsions Ten Years On. in Annual review of psychology

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

 
Description Modulation of impulsive behaviours by targeting metabotropic receptors
Amount £15,000 (GBP)
Funding ID RG66139 
Organisation Boehringer Ingelheim 
Sector Private
Country Germany
Start 10/2012 
End 09/2015
 
Description Consultancy agreement between Cambridge University technical services and Boehringer Ingelheim Pharma GmbH & Co. 
Organisation Boehringer Ingelheim
Country Germany 
Sector Private 
PI Contribution Cambridge will provide samples (brain, blood, CSF) from trait low and high impulsive rats.
Collaborator Contribution Boehringer Ingelheim will carry out large-scale gene expression profiling.
Impact N/A
Start Year 2012
 
Description BAP Residential Course, Cambridge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Lively and lengthy discussion. Attendees were able to visit an imaging facility

Difficult to assess beyond attendees receiving credits for the BAP training course.
Year(s) Of Engagement Activity 2014
 
Description Cheltenham Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 500+ attended. Lively discussion followed - moved to another location as questions continued for ~1 hour.

Notable interest of the public to learn about OCD, addiction and eating disoders
Year(s) Of Engagement Activity 2011
 
Description Invited lecture (Amsterdam) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Plenary talk - VUMC, Amsterdam. 200+ people (Faculty, post-docs, graduates). March 13th. "Jumping the gun: novel brain mechanisms and markers"

Strengthened collaborative links between Cambridge and the VUMC in Amsterdam
Year(s) Of Engagement Activity 2013
 
Description Invited lecture (Munich) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Plenary talk, Max Plank Institute of Psychiatry, Munich. "The neuroscience of impulse control: novel biomarkers and mechanisms". 250+.

Scientific networking and collaboration
Year(s) Of Engagement Activity 2013
 
Description Invited talk (Cambridge) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Cambridge Psychopharmacology Programme, Master Class: Latest Advances in Psychopharmacology, Cambridge, April 18-20th. Organised by Stephen Stahl. 500+. Talk title: "Brain circuits and addiction: substrates for potential new treatments for addiction"

Established several collaborations
Year(s) Of Engagement Activity 2013
 
Description NIDA-sponsored Addiction Workshop, Barcelona 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Long discussion and many questions

A podcast of the talk/workshop is available on YouTube.
Year(s) Of Engagement Activity 2014
 
Description Plenary talk (Ireland) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Annual Symposium, Institute of Neuroscience, Trinity College Dublin

Invited speakers participated in a Q&A session with doctoral and post-doctoral workers to discuss career options and current issues/hot topics in neuroscience.
Year(s) Of Engagement Activity 2012
 
Description Sciscreen public lecture (Cambridge) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact 100 people attended my talk on the brain science of addiction, which preceeded the movie "Trainspotting". Many questions were asked during an informal Q&A session after the movie.

Follow-up questions from the public (via email)
Year(s) Of Engagement Activity 2012
 
Description Symposium (USA) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact ~500 in attendence. Annual Meeting of the Biological Psychiatry Society, San Francisco, May 10th.
"Addiction biomarkers: translational approaches toward identifying risk and novel treatments"

Established a consultancy collaboration with Boehringer Ingelheim Pharma GmbH.
Year(s) Of Engagement Activity 2011
 
Description Symposium talk (Palm Springs) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact ~500 participanats. Annual International Meeting of the College on Problems of Drug Dependence (CPDD), Palm Springs, USA, June 11th

Established new collaborations
Year(s) Of Engagement Activity 2012