Cellular Basis of Nicotine Induced Aversion

描述(申请人提供)：尼古丁成瘾在美国和全世界仍然是一个主要的健康问题。尼古丁的有益作用是有据可查的，但高剂量的尼古丁会产生强烈的反感作用。对尼古丁的初始反应可以预测 未来依赖(即，与第一次尼古丁体验令人厌恶的受试者相比，第一次尼古丁体验是有回报的受试者更有可能成为尼古丁依赖者)。因此，尼古丁奖赏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相当大的了解，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研究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目标和策略。最近，从内侧缰核(MHB)到脚间核(IPN)的投射被证明参与了尼古丁厌恶。抑制MHB-IPN活性可以减少尼古丁的厌恶作用，而增强MHB-IPN活性则会增强对尼古丁的厌恶。尽管这些结果涉及MHB-IPN回路，但IPN的下游突触后靶点和所涉及的神经递质在很大程度上仍未确定。一些证据表明，这种回路最终会抑制VTA多巴胺(DA)神经元。DA神经元的突发性活动与动机行为有关，抑制DA神经元的输出会导致厌恶体验。虽然IPN投射到几个脑区，但它强烈支配被盖外侧背侧核(LDTg)，这是一个脑干胆碱能中心，控制VTA DA神经元的爆发放电。向VTA投射的LDTg神经元的激活导致VTA的活动增强和条件性位置偏爱，而VTA DA神经元的抑制与条件性位置厌恶有关。因此，抑制LDTg(通过IPN兴奋)，从而抑制VTA DA神经元，可能会减弱尼古丁的奖赏效应。这项提案中概述的实验将检查尼古丁厌恶效应背后的细胞机制，以及这种厌恶如何影响奖赏回路。我们将使用光遗传学策略来探索MHB-IPN通路和VTA DA神经元之间的通讯的细胞机制。在测试尼古丁相关行为的同时，将通过光遗传刺激或抑制这些途径来探索这些途径与尼古丁诱导行为之间的因果联系。探索MHB-IPN回路介导尼古丁厌恶的机制可以为帮助吸烟者成功戒烟提供新的治疗靶点和治疗策略。

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.