Cellular Basis of Nicotine Induced Aversion

尼古丁引起厌恶的细胞基础

• 批准号: 8722770
• 负责人: Daniel S McGehee
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722770
• 关键词: Animals; Area; Attenuated; Behavior; Behavioral Assay; Brain; Brain Stem; Cell Nucleus; Collaborations; Communication; Complex; Control Animal; Dependence; Development; Dopamine; Dorsal; Dose; Electrophysiology (science); Equilibrium; Experimental Designs; Future; Goals; Habenula; Halorhodopsins; Health; Laboratories; Lateral; Lead; Light; Link; Maintenance; Medial; Mediating; Monitor; Mus; Neurons; Neurotransmitter Receptor; Neurotransmitters; Nicotine; Nicotine Dependence; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Population; Presynaptic Terminals; Relative (related person); Reporting; Rewards; Role; Self Administration; Self-Administered; Slice; Smoker; Synapses; System; Testing; Time; Viral Vector; Work; base; cholinergic; conditioning; dopaminergic neuron; experience; in vivo; insight; interpeduncular nucleus; laterodorsal tegmentum; motivated behavior; neural circuit; new therapeutic target; novel; optogenetics; postsynaptic; preference; promoter; public health relevance; research study; response; reward circuitry; treatment strategy

DESCRIPTION (provided by applicant): Nicotine addiction remains a major health problem in the US and throughout the world. The rewarding effects of nicotine are well-documented, but higher doses of nicotine have intensely aversive effects. Initial responses to nicotine can predict future dependence (i.e., subjects whose first nicotine experiences were rewarding are more likely to become nicotine dependent relative to subjects whose first nicotine experiences were aversive). Thus, the balance between nicotine reward and aversion likely contributes to the development and maintenance of nicotine addiction. Despite considerable understanding of the effects of nicotine on reward-related circuitry, treatments for nicotine dependent populations remain limited. Understanding the mechanisms that underlie aversion to nicotine can provide novel insights into the factors that contribute to nicotine dependence. These insights have the potential to reveal novel therapeutic targets and strategies. Recently, the projection from the medial habenula (MHb) to the interpeduncular nucleus (IPN) was shown to mediate nicotine aversion. Suppressing MHb-IPN activity reduces the aversive effects of nicotine, while enhancing MHb-IPN activity enhances aversion to nicotine. Although these results implicate the MHb-IPN circuitry, the downstream post-synaptic targets of the IPN and the neurotransmitters involved remain largely uncharacterized. Some evidence suggests that this circuitry ultimately suppresses VTA dopamine (DA) neurons. Burst activity in DA neurons has been linked to motivated behaviors, and suppression of DA neuron output results in an aversive experience. While the IPN projects to several brain areas, it strongly innervates the lateral dorsal tegmental nucleus (LDTg), a brainstem cholinergic center that controls burst firing of VTA DA neurons. Activation of LDTg neurons that project to the VTA results in enhanced activity in the VTA as well as conditioned place preference, whereas inhibition of VTA DA neurons has been linked to conditioned place aversion. Therefore, inhibiting the LDTg (via IPN excitation), and consequently VTA DA neurons, may diminish the rewarding effects of nicotine. Experiments outlined in this proposal will examine the cellular mechanisms underlying the aversive effects of nicotine and how this aversion impacts reward circuitry. We will use optogenetic strategies to explore the cellular mechanisms mediating the communication between the MHb-IPN pathway and VTA DA neurons. Causal links between these pathways and nicotine-induced behaviors will be explored by optogenetic excitation or inhibition of these pathways while testing nicotine-related behaviors. Exploring the mechanisms by which the MHb-IPN circuitry mediates nicotine-aversion could yield novel therapeutic targets and treatment strategies for helping smokers quit successfully.

描述（由申请人提供）：尼古丁成瘾仍然是美国和全世界的一个主要健康问题。尼古丁的有益作用已被充分证明，但较高剂量的尼古丁会产生强烈的厌恶作用。对尼古丁的初步反应可以预测 未来依赖（即，相对于第一次尼古丁体验令人厌恶的受试者，首次尼古丁体验有益的受试者更有可能变得尼古丁依赖）。因此，尼古丁奖励和厌恶之间的平衡可能有助于尼古丁成瘾的发展和维持。尽管人们对尼古丁对奖赏相关回路的影响有了相当多的了解，但对尼古丁依赖人群的治疗仍然有限。了解厌恶尼古丁的机制可以为导致尼古丁依赖的因素提供新的见解。这些见解有可能揭示新的治疗靶点和策略。 最近，从内侧缰核（MHb）到脚间核（IPN）的投射被证明可以介导尼古丁厌恶。抑制 MHb-IPN 活性可减少尼古丁的厌恶作用，而增强 MHb-IPN 活性则可增强对尼古丁的厌恶。尽管这些结果暗示了 MHb-IPN 回路，但 IPN 的下游突触后靶标和所涉及的神经递质在很大程度上仍然未知。一些证据表明，该电路最终会抑制 VTA 多巴胺 (DA) 神经元。 DA 神经元的爆发活动与动机行为有关，抑制 DA 神经元输出会导致厌恶的体验。虽然 IPN 投射到多个大脑区域，但它强烈支配外侧背侧被盖核 (LDTg)，这是一个控制 VTA DA 神经元爆发放电的脑干胆碱能中心。激活投射到 VTA 的 LDTg 神经元会导致 VTA 活动增强以及条件性位置偏好，而 VTA DA 神经元的抑制则与条件性位置厌恶相关。因此，抑制 LDTg（通过 IPN 兴奋），进而抑制 VTA DA 神经元，可能会减弱尼古丁的奖励作用。 该提案中概述的实验将检查尼古丁厌恶作用背后的细胞机制以及这种厌恶如何影响奖励回路。我们将利用光遗传学策略来探索介导 MHb-IPN 通路与 VTA DA 神经元之间通讯的细胞机制。在测试尼古丁相关行为时，将通过这些途径的光遗传学激发或抑制来探索这些途径与尼古丁诱导的行为之间的因果关系。探索 MHb-IPN 电路介导尼古丁厌恶的机制可能会产生新的治疗靶点和治疗策略，帮助吸烟者成功戒烟。