Adolescent nicotine-induced enhancement of adult morphine reward: mediation by midbrain inhibitory circuits

项目摘要 阿片类药物滥用仍然是美国可预防死亡的主要原因之一1。一些 这些因素导致了这一严重的公共卫生问题，先前的尼古丁使用是一个重要但很差的因素。 了解风险因素2.尼古丁是烟草制品的主要成瘾成分，包括电子烟。 香烟，吸烟在吸毒者中特别普遍3。尽管人类流行病学 研究表明青少年尼古丁使用与未来阿片类药物滥用有关4，潜在的大脑机制仍然存在 不清楚为了解决这一科学空白，这项建议调查了神经生物学基础， 青少年尼古丁使用与成人阿片类药物滥用。与文献5一致，我们的飞行员行为数据 研究表明，在青春期接受尼古丁治疗的小鼠对吗啡配对的偏好增强， 条件性位置偏好（CPP）范式。作为这种行为的潜在神经基质， 腹侧被盖区（VTA）是一个异质性的中脑核团，由多巴胺和多巴胺组成。 和GABA神经元，这是必不可少的奖励处理和药物相关的行为6 -9。扩建这幢 根据文献，Dani实验室先前的工作表明，青少年时期的尼古丁暴露 发育窗口产生VTA GABA神经元功能的持续变化， 寻找10.作为这种尼古丁诱导的腹侧被盖区神经适应的证据，我们的飞行员的电生理学 结果表明，吗啡对腹侧被盖区GABA神经元的药理作用（即抑制）是 青少年尼古丁治疗的矛盾逆转（即兴奋）。GABA神经元功能的变化 与吗啡奖励的关系仍然未知。出于这些原因，本提案检验了总体假设 青少年尼古丁通过改变吗啡诱导的VTA GABA兴奋性促进成年吗啡奖赏 神经元为了验证这一假设，我提出的项目整合了体外电生理学，体内化学遗传学， 操作和行为药理学，以询问腹侧被盖区GABA神经元兴奋性在 青少年尼古丁诱导的吗啡奖赏增强。具体而言，目标1描述了 青少年尼古丁对VTA中吗啡诱导的抑制信号的影响。目标2确定了畸变的作用 青少年尼古丁暴露引起的VTA GABA神经元活动在驱动吗啡CPP升高中的作用 总的来说，这项工作的结果将提供深入了解尼古丁引起的吗啡滥用的神经基础 并将进一步告知我们对药物奖励处理中中脑可塑性的理解。这笔赠款将 还提供了一个有抱负的独立的科学家在大学的一个杰出的环境至关重要的培训 宾夕法尼亚州。特别是，这一建议是实现申请人职业目标的关键一步， 领导她自己的实验室，将全面，均衡的培训计划与创新的 研究青少年尼古丁诱导成人VTA GABA神经元兴奋性的作用 阿片类药物滥用

Project Summary Opioid abuse remains one of the leading causes of preventable death in the United States1. A number of elements contribute to this serious public health problem, with prior nicotine use being an important yet poorly understood risk factor2. Nicotine is the main addictive component of tobacco products, including electronic cigarettes, use of which is particularly prevalent among adolescents3. Despite compelling human epidemiological studies linking adolescent nicotine use with future opioid abuse4, the underlying brain mechanisms remain unclear. To address this scientific gap, this proposal investigates the neurobiological underpinnings linking adolescent nicotine use with adult opioid abuse. Consistent with the literature5, our pilot behavioral data demonstrate that mice treated with nicotine in adolescence show enhanced preference for a morphine-paired context in the conditioned place preference (CPP) paradigm. As a potential neural substrate of this behavioral interaction, the ventral tegmental area (VTA) is a heterogeneous midbrain nucleus, consisting of both dopamine and GABA neurons, that is essential for reward processing and drug-related behaviors6-9. Extending this literature, prior work from the Dani Lab demonstrated that nicotine exposure during the adolescent developmental window produces a persistent change in VTA GABA neuron function that drives enhanced drug seeking10. As evidence of such nicotine-induced neural adaptations in the VTA, our pilot electrophysiological results revealed that the pharmacological effect of morphine on VTA GABA neurons (i.e. inhibition) is paradoxically inverted (i.e. excitation) by adolescent nicotine treatment. How changes in GABA neuron function relate to morphine reward remain unknown. For these reasons, this proposal tests the overarching hypothesis that adolescent nicotine promotes adult morphine reward via altered morphine-induced excitability of VTA GABA neurons. To test this hypothesis, my proposed project integrates ex vivo electrophysiology, in vivo chemogenetic manipulations, and behavioral pharmacology to interrogate the role of VTA GABA neuron excitability in adolescent nicotine-induced heightened morphine reward. Specifically, Aim 1 characterizes the effect of adolescent nicotine on morphine-induced inhibitory signaling in the VTA. Aim 2 determines the role of aberrant VTA GABA neuron activity, arising from adolescent nicotine exposure, in driving heightened morphine CPP. Collectively, the results of this work will provide insight into the neural basis of nicotine-induced morphine abuse liability and will further inform our understanding of midbrain plasticity in drug reward processing. This grant will also provide crucial training for an aspiring independent scientist in an outstanding environment at the University of Pennsylvania. In particular, this proposal represents a critical step in attaining the applicant’s career goal of leading her own laboratory by combining a comprehensive, well-balanced training plan with an innovative program of research to investigate the role of VTA GABA neuron excitability in adolescent nicotine-induced adult opioid abuse.