Investigating the mechanisms underlying cholinergic regulation of dopamine release
Lead Research Organisation:
University of Oxford
Department Name: Interdisciplinary Bioscience DTP
Abstract
The neurotransmitter dopamine plays a fundamental role in regulating motor and motivational functions. Disruptions to its signalling underlie several psychomotor disorders, including Parkinson's disease, and addiction disorders. Interestingly, dopamine neurons form highly branched and complex axons, generating a surprisingly high number of synapses, bigger than most other neurons in the central nervous system. These peculiar features suggest that the correspondence between dopamine neuron activation and neurotransmitter release at the synapse is a complex process, regulated by local axonal mechanisms. It is known that a major modulator is acetylcholine, which acts to gate dopamine release at nicotinic acetylcholine receptors localised on dopaminergic axons. These receptors are also the target of exogenous substances, such as nicotine. Despite the high relevance, the underlying mechanisms through which these nicotinic receptors control dopamine release have not been fully unveiled. It is therefore fundamental to understand in deeper detail how this pathway influences dopamine release in the brain, in order to develop potential strategies when such pathway is dysregulated, such as in addiction disorders. This project aims at better defining the modalities of nicotinic receptor regulation of dopamine release and at identifying specific pathways that could be acting downstream of these receptors. We will adopt a rodent model and electrochemical techniques (fast-scan cyclic voltammetry, amperometry) for the detection of released dopamine to shed light on such fundamental questions.
BBSRC priority areas:
The proposed research project addresses the BBSRC cross-council priorities of brain science and mental health, together with a research approach consistent with the BBSRC priority area of replacement, refinement and reduction (3Rs) of animal use in research, welfare of managed animals and bioscience underpinning health.
BBSRC priority areas:
The proposed research project addresses the BBSRC cross-council priorities of brain science and mental health, together with a research approach consistent with the BBSRC priority area of replacement, refinement and reduction (3Rs) of animal use in research, welfare of managed animals and bioscience underpinning health.
Publications
Brimblecombe KR
(2019)
Calbindin-D28K Limits Dopamine Release in Ventral but Not Dorsal Striatum by Regulating Ca2+ Availability and Dopamine Transporter Function.
in ACS chemical neuroscience
Condon MD
(2019)
Plasticity in striatal dopamine release is governed by release-independent depression and the dopamine transporter.
in Nature communications
Description | Preliminary results indicate that there's a limited relationship between activity and release of acetylcholine and the regulation of dopamine release, suggesting that nicotinic acetylcholine receptors are the major regulators of dopamine release, insightful to better understand specific aspects of nicotine addiction. |
Exploitation Route | This work will provide information about striatal acetylcholine transmission properties, which are currently undefined, that could be informative for investigating cholinergic circuits in multiple brain areas. Furthermore, the properties and downstream mechanisms of nicotinic acetylcholine receptors will also be investigated, informing about potential therapeutic targets. |
Sectors | Pharmaceuticals and Medical Biotechnology |
Description | BBSRC in vivo skills award |
Amount | £15,000 (GBP) |
Funding ID | DDT00060 AV01.05 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2019 |
End | 09/2021 |
Description | Collaboration to investigate a potential relationship between diabetes and increased risk of Parkinson's Disease |
Organisation | Institute of Biomedical Research Alberto Sols |
Country | Spain |
Sector | Academic/University |
PI Contribution | We tested whether striatal dopamine release was altered in two mouse models of diabetes (type 1 and 2) using fast-scan cyclic voltammetry. |
Collaborator Contribution | The partner's lab designed the study and carried out experiments testing whether the levels of expression of proteins associated with the regulation of dopamine neurotransmission in the striatum were altered in the diabetes models. |
Impact | This collaboration resulted into a manuscript currently in revision at Movement Disorders. |
Start Year | 2019 |