Investigating the mechanisms underlying cholinergic regulation of dopamine release

神经递质多巴胺在调节运动和动机功能中起着重要作用。对其信号的破坏是几种精神运动障碍的基础，包括帕金森氏病和成瘾障碍。有趣的是，多巴胺神经元形成高度分支和复杂的轴突，产生数量惊人的突触，比中枢神经系统中大多数其他神经元都要大。这些奇特的特征表明，多巴胺神经元激活和突触神经递质释放之间的对应关系是一个复杂的过程，受局部轴突机制的调节。已知乙酰胆碱是一种主要的调节剂，其作用是控制多巴胺能轴突上的尼古丁乙酰胆碱受体释放多巴胺。这些受体也是外源性物质（如尼古丁）的目标。尽管相关性很高，但这些尼古丁受体控制多巴胺释放的潜在机制尚未完全揭示。因此，更深入地了解这一途径如何影响大脑中多巴胺的释放是至关重要的，以便在这一途径失调时制定潜在的策略，比如在成瘾障碍中。该项目旨在更好地确定尼古丁受体调节多巴胺释放的方式，并确定可能在这些受体下游发挥作用的特定途径。我们将采用啮齿动物模型和电化学技术（快速扫描循环伏安法，安培法）来检测释放的多巴胺，以阐明这些基本问题。BBSRC优先领域：拟议的研究项目涉及BBSRC跨委员会的脑科学和心理健康优先领域，以及与BBSRC研究中动物使用的替代、改进和减少（3Rs）、管理动物的福利和支撑健康的生物科学优先领域一致的研究方法。

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.