Nicotine mitigates dopamine blockade-induced aberrant plasticity and learning

尼古丁减轻多巴胺阻断引起的异常可塑性和学习

• 批准号: 8633066
• 负责人: Xiaoxi Zhuang
• 金额: $ 22.91万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633066
• 关键词: Acute; Affinity; Chronic; Corpus striatum structure; Data; Denervation; Dependovirus; Dopamine; Dopamine Receptor; Dorsal; Down-Regulation; Epidemiologic Studies; Figs - dietary; Financial compensation; Genetic; Goals; Home environment; Incidence; Knock-out; Learning; Literature; Long-Term Potentiation; Modeling; Motor; Motor output; Movement; Mus; Neurons; Nicotine; Nicotinic Receptors; Parkinson Disease; Pathway interactions; Performance; Phase; Population; Publishing; Signal Transduction; Smoker; Smoking; Symptoms; Synaptic plasticity; Testing; Therapeutic; Time; Work; base; desensitization; dopaminergic neuron; experience; in vivo; motor learning; neurotensin mimic 2; postsynaptic; prevent; protective effect; public health relevance

DESCRIPTION (provided by applicant): Epidemiological studies have consistently shown that the incidence of Parkinson's disease (PD) is reduced in smokers. However, the mechanism by which smoking acts to reduce the incidence of PD remains unknown. Our earlier studies have demonstrated that dopamine (DA) blockade promotes increased activity of the inhibitory, indirect pathway leading to learned inhibition of movement, a phenomenon that we term 'aberrant motor learning.' In this application, we aim to test the hypothesis that chronic nicotine by desensitizing ¿2-containing nAChRs, prevents such aberrant learning and lessens PD symptoms. Specific Aim 1 will dissociate whether ¿2 deactivation on DA neurons is sufficient to block aberrant motor learning and whether the specific deletion of this population of ¿2-containing nAChRs prevents the initial acquisition of aberrant learning during DA receptor blockade or facilitates the acquisition of new learning once DA signaling is restored. Specific Aim 2 will delineate the mechanism by which chronic nicotine, acting via ¿2-containing nAChRs, blocks aberrant learning. Given that nicotine administered over a period of time significantly alters DA release, we will test the hypothesis that such adaptive changes have protective effects against aberrant synaptic plasticity induced by DA blockade.

描述（由申请人提供）：流行病学研究一致表明，吸烟者帕金森病（PD）的发病率降低。然而，吸烟降低帕金森病发病率的机制仍不清楚。我们早期的研究表明，多巴胺 (DA) 阻断会促进抑制性间接途径的活动增加，从而导致习得性运动抑制，这种现象我们称之为“异常运动学习”。在本申请中，我们的目的是测试这样的假设：慢性尼古丁通过使含有 ¿2 的 nAChR 脱敏，可以防止这种异常学习并减轻 PD 症状。具体目标 1 将分离 DA 神经元上的 ¿2 失活是否足以阻止异常运动学习，以及含有 ¿2 的 nAChR 群体的特定删除是否会阻止 DA 受体阻断期间异常学习的初始获得，或者一旦 DA 信号恢复则促进新学习的获得。具体目标 2 将描述慢性尼古丁通过含有 ¿2 的 nAChR 起作用、阻止异常学习的机制。鉴于在一段时间内施用尼古丁会显着改变 DA 释放，我们将检验这样的假设：这种适应性变化对 DA 阻断引起的异常突触可塑性具有保护作用。