Cellular Basis of Nicotine Induced Aversion

尼古丁引起厌恶的细胞基础

• 批准号: 8830958
• 负责人: Daniel S McGehee
• 金额: $ 35.03万
• 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/8830958
• 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; 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主要健康问题。尼古丁的有益作用是有据可查的，但较高剂量的尼古丁具有强烈的厌恶作用。对尼古丁的最初反应可以预测 未来的依赖性（即，与第一个尼古丁经历的受试者相对于尼古丁经历的尼古丁的依赖，他们的第一个尼古丁经历的受试者更有可能成为尼古丁。因此，尼古丁奖励与厌恶之间的平衡可能有助于尼古丁成瘾的发展和维持。尽管对尼古丁对奖励相关电路的影响有很高的了解，但对尼古丁依赖性种群的治疗仍然有限。了解对尼古丁厌恶的机制可以提供对有助于尼古丁依赖性的因素的新见解。这些见解有可能揭示新的治疗靶标和策略。 最近，显示从内侧Habenula（MHB）到枝间核（IPN）的投影显示介导尼古丁厌恶。抑制MHB-IPN活性降低了尼古丁的厌恶作用，同时增强MHB-IPN活性会增强对尼古丁的厌恶。尽管这些结果暗示了MHB-IPN电路，但IPN和涉及神经递质的下游突触后靶标在很大程度上仍然没有表征。一些证据表明，该电路最终抑制了VTA多巴胺（DA）神经元。 DA神经元中的爆发活动与动机行为有关，DA神经元输出的抑制会导致厌恶经历。当IPN投射到几个大脑区域时，它强烈影响了背侧侧核（LDTG），这是一个控制VTA DA神经元爆发的脑干胆碱能中心。向VTA投射的LDTG神经元的激活导致VTA的活性增强以及条件的位置偏好，而对VTA DA神经元的抑制已与条件的位置厌恶息息相关。因此，抑制LDTG（通过IPN激发），因此可以抑制VTA DA神经元，可能会减少尼古丁的奖励作用。 该提案中概述的实验将检查尼古丁厌恶作用的基础机制，以及这种厌恶如何影响奖励电路。我们将使用光遗传策略来探索介导MHB-IPN途径与VTA DA神经元之间通信的细胞机制。这些途径与尼古丁诱导的行为之间的因果关系将通过光遗传激发或对这些途径的抑制进行探索，同时测试与尼古丁相关的行为。探索MHB-IPN电路介导尼古丁避孕的机制可以产生新颖的治疗靶标和治疗策略，以帮助吸烟者成功戒烟。