Identifying the alpha6 nicotinic receptor subtypes that govern the control of striatal dopamine transmission by nicotine

Lead Research Organisation: University of Oxford
Department Name: Physiology Anatomy and Genetics

Abstract

Tobacco smoking is one of the largest preventable causes of illness and death worldwide. The Royal College of Physicians have estimated that smoking-related ill health generates at least 1,000 hospital admissions per day in England alone, and is the cause of a fifth of all UK deaths. Although these detrimental effects on our health can readily be prevented by stopping smoking, in practice as any smoker knows, giving up the habit is difficult. Smoking is addictive. We urgently need to improve the means available to smokers to aid their chances of extinguishing a smoking habit once and for all. In order to do this it is essential that we improve our understanding of the fundamental mechanisms of how nicotine acts in the brain. We already know that like cocaine and amphetamine, nicotine is addictive because it increases levels of the neurochemical dopamine in brain centres related to reward where nicotine mimics the effects of natural rewards. But we do not understand how nicotine can do this. In particular, we have still not fully identified the molecules, or neurochemical receptors, on nerve cell membranes that nicotine binds to and that are responsible for enhancing dopamine in these reward centres.
The work we propose will identify which of nicotine?s many receptors are the receptors central to nicotine?s addictive properties. We will deduce which receptors are most important by using a state-of-the-art method to detect the effects of nicotine on dopamine in these brain centres in mice who carry different types of these receptors. If we can identify the right receptor, we will have found a target site for action for a future pharmaceutical treatment to combat nicotine addiction.

Technical Summary

Nicotine addiction through tobacco smoking is amongst the largest single preventable causes of morbidity and premature mortality in the world. Yet, we still lack complete knowledge of the fundamental neuronal mechanisms underlying nicotine action, and certainly lack definitive treatments for nicotine addiction. Striatal dopamine transmission is a key player in the development of nicotine addiction. Despite detailed characterization of the diverse stoichiometries of the heteromeric nicotinic receptors expressed within striatum, little is known about the functional relevance of each receptor type in nicotine?s actions. Alpha6-subunit-containing (alpha6*) receptors are attracting much attention as promising targets for pharmacotherapies in dopaminergic disorders because unlike other subunits, their expression is relatively restricted to dopamine neurons. Moreover, we now have unpublished data to suggest that alpha6*-receptors play a previously unappreciated dominant role in the control of dopamine neurotransmission by nicotine in the nucleus accumbens (Exley et al., submitted).
Alpha6*-receptors are proposed to exist in three forms variously containing alpha4 and beta3 co-subunits (Salminen et al., 2007). In this project, we will identify the alpha6*-receptors responsible for the control of striatal dopamine neurotransmission by nicotine and endogenous acetylcholine. The effects of nicotine on dopamine neurotransmission depend critically on endogenous striatal acetylcholine (Rice and Cragg 2004, Cragg 2006). We will use real-time electrochemical technologies, namely fast-scan cyclic voltammetry to detect synaptic dopamine transients with subsecond time resolution at carbon-fibre microelectrodes in acutely living slices of mouse striatum where acetylcholine neuron activity is intact. We will identify the function of the diverse portfolio of alpha6*-receptors in the control of dopamine neurotransmission using transgenic mice with subunit-specific deletions (alpha6, alpha4, beta3) in combination with pharmacological tools. Since nicotinic receptor control of dopamine transmission is specific to the frequency of action potentials reaching the dopamine synapse (Rice and Cragg 2004; Zhang and Sulzer 2004), the design of these experiments will necessarily involve exploring dopamine transients released across the range of physiologically relevant activity in dopamine neurons including low frequency tonic ( 10 Hz) and high-frequency reward-related activity (20-100 Hz).
These experiments should reveal the identity (alpha and beta subunit composition) of the alpha6-receptors responsible for the powerful control of endogenous dopamine neurotransmission by nicotine. These data will not only enhance our understanding of nicotine?s synaptic mechanisms of action but moreover, should also provide a key therapeutic target for the design of pharmaceutical strategies to treat nicotine addiction as well as other disorders of dopamine dysfunction including Parkinson?s disease.

Publications

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Brimblecombe KR (2015) Substance P Weights Striatal Dopamine Transmission Differently within the Striosome-Matrix Axis. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Dodson PD (2016) Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism. in Proceedings of the National Academy of Sciences of the United States of America

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Exley R (2008) Alpha6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens. in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

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Exley R (2012) Striatal a5 nicotinic receptor subunit regulates dopamine transmission in dorsal striatum. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Exley R (2011) Distinct contributions of nicotinic acetylcholine receptor subunit alpha4 and subunit alpha6 to the reinforcing effects of nicotine. in Proceedings of the National Academy of Sciences of the United States of America

 
Description BBSRC DTP DPhil SVM
Amount £90,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2018 
End 09/2021
 
Description Clarendon Fund Studentship 2011
Amount £100,000 (GBP)
Organisation University of Oxford 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description DPhil Studentship BR
Amount £110,000 (GBP)
Organisation University of Oxford 
Department Clarendon Fund
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description FORMA collaboration
Amount £300,000 (GBP)
Organisation FORMA Therapeutics 
Sector Private
Country United States
Start 05/2019 
End 04/2021
 
Description IBRO Studentship
Amount £10,000 (GBP)
Organisation International Brain Research Organisation (IBRO) 
Sector Academic/University
Country Global
Start 10/2007 
End 03/2008
 
Description MRC Project grant KJ 2012
Amount £369,497 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 11/2012 
End 10/2015
 
Description MRC iCASE DPhil Studentship
Amount £120,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 09/2022
 
Description MRC-DTA DPhil Studentship 2009
Amount £61,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2012
 
Description MRC-DTA DPhil studensthip 2010
Amount £61,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 09/2013
 
Description MSD DPhil funding competition - Peter Kilfeather
Amount £85,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2020
 
Description Monument Trust Discovery Award 2010
Amount £5,000,000 (GBP)
Funding ID J-0901 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2010 
End 02/2015
 
Description Monument Trust Discovery Award Renewal 2015
Amount £5,800,000 (GBP)
Funding ID J-1403 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2015 
End 02/2020
 
Description NSF Fellowship LB
Amount $200,000 (USD)
Organisation National Science Foundation (NSF) 
Sector Public
Country United States
Start 08/2018 
End 07/2021
 
Description Parkinson's Disease UK Project Grant 2008
Amount £164,250 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2008 
End 03/2012
 
Description Parkinson's Disease UK Project Grant 2008
Amount £177,083 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2008 
End 08/2011
 
Description Parkinson's UK Innovation Grant 2013
Amount £34,986 (GBP)
Funding ID K-1209 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 12/2013
 
Description Parkinson's UK PhD Studentship 2010
Amount £92,993 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2010 
End 10/2013
 
Description Parkinson's UK Project Grant 2011
Amount £145,451 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2011 
End 07/2013
 
Description Parkinson's UK Project Grant 2015
Amount £297,158 (GBP)
Funding ID G-1504 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2016 
End 12/2018
 
Description Parkinson's UK Project Grant 2017 Magill PFFs
Amount £218,701 (GBP)
Funding ID G-1702 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2018 
End 02/2021
 
Description Rhodes Scholarship 2013
Amount £70,000 (GBP)
Organisation Rhodes Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Title Stimulation protocol 
Description An approach to studying the control of striatal dopamine transmissoin, that uses a novel but key range of stimulus parameters that exposes powerful and activity-dependent mechanisms that control of transmission. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? Yes  
Impact Has aided understanding of other striatal systems e.g. opioid receptor function (Britt and McGehee, Journal of Neuroscience, 2008), D2 and nachrs (Zhang et al 2009, Mol Pharmacol; Zhang et al 2010, J Neurosci) 
 
Title ChI neuron model IKr 
Description NEURON based model for a cholinergic interneuron, encompassing IKr 
Type Of Material Computer model/algorithm 
Year Produced 2018 
Provided To Others? Yes  
Impact Published paper: Zhang et al (2018) Neuron, 98:918-925 
URL https://github.com/Yanfeng-Zhang/Pause-in-ChIs-Neuron-model
 
Description A53T synuclein 
Organisation Goethe University Frankfurt
Department Department of Neurology
Country Germany 
Sector Academic/University 
PI Contribution Study of DA synapse fucntion in mouse model of PD
Collaborator Contribution Supply of A53T-PrP transgenic mouse model of Parkinson's disease
Impact Poster presentations at Meeting of Parkinson's UK, York 2010
Start Year 2009
 
Description Alpha5 
Organisation Pasteur Institute, Paris
Department Department of Neuroscience
Country France 
Sector Academic/University 
PI Contribution Study of function of alpha5 subunits in nicotinic receptor control of dopamine transmission
Collaborator Contribution SUpply of novel transgenic animals and vectors
Impact Publication Exley et al 2012 New grant funded by Parkinson's UK
Start Year 2011
 
Description Cerevance 
Organisation Cerevance Ltd
PI Contribution Study of new pipeline ligands. Partner for MRC iCASE award
Collaborator Contribution Supply of new pipeline ligands Partner for MRC iCASE award
Impact New MRC iCASE studentship
Start Year 2017
 
Description Ewing lab mass spec 
Organisation Chalmers University of Technology
Country Sweden 
Sector Academic/University 
PI Contribution Supply of intellectual question, background data and brain tissue
Collaborator Contribution Mass spec analysis
Impact Manuscript in preparation
Start Year 2017
 
Description John Lowry 
Organisation Maynooth University
Country Ireland 
Sector Academic/University 
PI Contribution Using new choline probes to explore striatal ACh function
Collaborator Contribution Manufacture and supply of choline probes
Impact New research effort and avenue
Start Year 2017
 
Description Muscarinic receptor function 
Organisation National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Country United States 
Sector Public 
PI Contribution Exploration of muscarinic receptor control of striatal dopamine release
Collaborator Contribution Supply of muscarinic receptor knockout mice
Impact Mansucript by Threlfell et al 2010 Journal of Neuroscience
Start Year 2008
 
Description Oxford Parkinson's Disease Centre 
Organisation University of Oxford
Department MRC Anatomical Neuropharmacology Unit
Country United Kingdom 
Sector Public 
PI Contribution STudy of dopamine synapse function in novel animal models of Parkinson's disease
Collaborator Contribution Supply of novel transgenic animal models of PD, study of accompanying pathology, imaging of affected pathways,
Impact MAnuscripts published, and abstracts presented at national and international meetings. This is a major multidisciplinary collaboration (£10million total income) to fund a research centre (Oxford Parkinson's Disease Centre)
Start Year 2010
 
Description Study of synuclein function and BAC transgenic models of Parkinson's disease 
Organisation University of Oxford
Department Department of Physiology, Anatomy and Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution Study of dopamine synapse function
Collaborator Contribution Supply of novel genotypes and mouse models of Parkinson's disease
Impact Senior et al, Eur J Neurosci, 2007 Janezic et al Taylor et al
 
Description University of Copenhagen, Perrier, spinal cord 
Organisation University of Copenhagen
Department Department of Neuroscience and Pharmacology (DNP)
Country Denmark 
Sector Academic/University 
PI Contribution Study of 5-HT transmission in spinal cord
Collaborator Contribution Study of 5-HT actions
Impact Published paper PMID 23487756
Start Year 2012
 
Description Use of alpha-conotoxin 
Organisation Cognetix
Country United Kingdom 
Sector Private 
PI Contribution We use the toxin supplied by Cognetix to investigate the role of alpha6-subunit-containing receptors in the control of striatal dopamine transmission
Collaborator Contribution Supply of key pharmacological agents
Impact Contributes towards findings that have been publihsed (Exley et al., 2008; Threlfell et al., 2010, Exley et al 2012)
Start Year 2006
 
Description alpha-4 and alpha-6 knockouts 
Organisation Pasteur Institute, Paris
Country France 
Sector Academic/University 
PI Contribution We undertake neurochemical investigations in these mice to identify the function of these specific nicotinic receptors
Collaborator Contribution Supply of key transgenic animals
Impact Contributes towards findings that have been presented at meetings, are in manuscripts under review and will form basis of new applications. Work also informs other ongoing research in the lab
Start Year 2008
 
Description Brain Awareness week 2013 RE 1 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact talk sparked questions and discussion afterwards

Unknown
Year(s) Of Engagement Activity 2013
 
Description Brain Awareness week 2013 RE 2 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact encouraged discussions about how the brain works and greater awareness of diseases such as PD and effects of tobacco

Unknown
Year(s) Of Engagement Activity 2013
 
Description Discuss Parkinson's research with individual fundraisers (DB, EL, SB) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Engagement with small groups of charitable donors to promote fundraising into Parkinson's research
Year(s) Of Engagement Activity 2009,2016,2017
 
Description Edinburgh International Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Talk sparked questions and debate

N/A
Year(s) Of Engagement Activity 2015
URL http://www.sciencefestival.co.uk/mediaLibrary/other/english/6285.pdf
 
Description FENS Ambassador interview 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Interview by an Ambassador to the Federation of European Neuroscience Societies for Facebook live interview, to give briefly discuss y lab's work and to give advice to postgraduate students
Year(s) Of Engagement Activity 2018
URL https://www.facebook.com/FENSorg/videos/2118188164876552
 
Description Guest speaker at 25th Anniversary tea party, Newbury Parkinson's group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Guest speaker on disease research at anniversary tea party for Newbury Parkinson's group which sparked lively debate and questions and interest
Year(s) Of Engagement Activity 2017
 
Description Host lab visits for Chinese students for Oxford Prospects Programme 
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Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Host lab visits for Chinese students for Oxford Prospects Programme
Year(s) Of Engagement Activity 2017
 
Description International Innovations article 2014 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Publication in internationally reaching magazine.
results not yet clear.

Not yet clear
Year(s) Of Engagement Activity 2014
URL http://www.internationalinnovation.com/hope-for-dopamine-disorders/
 
Description Interviewed by local radio station 2009 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Interviewed about use of nicotine in Parkinson's disease

N/A
Year(s) Of Engagement Activity 2009
 
Description Keynote speaker on Career, DPAG Postdoc Day, Oxford 
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Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Invited to discuss career path as part of a postdoctoral scientist development day
Year(s) Of Engagement Activity 2017
 
Description Neuroscience exhibition in the Oxford museum of Science March 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Neuroscience exhibition in the Oxford museum of Science March 2014


Unknown
Year(s) Of Engagement Activity 2014
 
Description Parkinson's group talk Hereford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Share knowledge, stimulate interest

After the talk, audience asked to visit lab
Year(s) Of Engagement Activity 2015
 
Description Public visit 2009 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Host science visit to members of the Parkinson's disease Society

N/A
Year(s) Of Engagement Activity 2009
 
Description School teaching BR MCS 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Catalysing interest in neuroscience
Year(s) Of Engagement Activity 2017,2018,2019
 
Description School visit to lab - Akeley Wood 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 20 pupils attended for a school visit to the research organisation which sparked questions and discussions
Year(s) Of Engagement Activity 2017
 
Description Skype a scientist LB 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Inform about career in neuroscience
Year(s) Of Engagement Activity 2018
URL https://www.skypeascientist.com/
 
Description Smarter UK 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Schools
Results and Impact KS3 talks about cognitive enhancing drugs

Not known
Year(s) Of Engagement Activity 2012
 
Description Speaker and Opening of fundraising walk for Parkinson's UK, Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Supporters
Results and Impact Speaker and Opening of fundraising walk for Parkinson's UK, Oxford
Year(s) Of Engagement Activity 2016
URL https://www.parkinsons.org.uk/content/walk-parkinsons
 
Description Talk at Stowe School to A-Level Medical Society on dopamine and careers in science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact We attended a school to talk about science and careers in science which sparked questions and discussion
Year(s) Of Engagement Activity 2017
 
Description UNIQ summer school 2013 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Schools
Results and Impact 30 pupils attended a week-long course, I hosted a dinner and workshop with Q&A

Not yet known
Year(s) Of Engagement Activity 2013
URL http://www.uniq.ox.ac.uk/
 
Description Wow!How? Stall 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact science fair at the Oxford University of Museum of Natural History

Not known
Year(s) Of Engagement Activity 2012