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。一批 一些因素导致了这一严重的公共卫生问题，以前使用尼古丁是一个重要但不利的因素 了解风险因素2。尼古丁是烟草产品的主要成瘾成分，包括电子烟。 香烟，在青少年中特别流行3。尽管有令人信服的人类流行病学 将青少年尼古丁使用与未来阿片类药物滥用联系起来的研究表明，潜在的大脑机制仍然存在 不清楚。为了解决这一科学鸿沟，这项提案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 证明在青春期接受尼古丁治疗的小鼠表现出对吗啡配对的更强的偏好 条件性位置偏好(CPP)范式中的语境。作为这种行为的潜在神经底物 相互作用时，腹侧被盖区(VTA)是一个异质的中脑核团，由两个多巴胺组成 和GABA神经元，这是奖赏处理和药物相关行为所必需的6-9。延续这一点 文献，丹尼实验室先前的工作表明，在青少年时期接触尼古丁 发育窗导致VTA GABA神经元功能持续变化，驱动增强型药物 寻找10。作为尼古丁诱导的VTA神经适应的证据，我们的飞行员电生理 结果表明，吗啡对VTA-GABA神经元的药理作用(即抑制)是 青春期尼古丁治疗反转(即兴奋)。GABA神经元功能的变化 与吗啡奖赏有关的问题仍不清楚。出于这些原因，这一提议检验了总体假设 青少年尼古丁通过改变吗啡诱导的VTA-GABA兴奋性促进成人吗啡奖赏 神经元。为了验证这一假设，我提出的项目将体外电生理学、体内化学发生 操作和行为药理学，以询问VTA GABA神经元兴奋性在 青春期尼古丁诱导的吗啡奖赏增加。具体地说，目标1描述了 青春期尼古丁对吗啡诱导的VTA抑制信号的影响。目标2决定了异常的作用 青少年尼古丁暴露引起的VTA GABA神经元活性，在驱动吗啡CPP升高的过程中。 总而言之，这项工作的结果将提供对尼古丁诱导的吗啡滥用的神经基础的洞察 并将进一步加深我们对药物奖励加工过程中中脑可塑性的理解。这笔赠款将 还在大学杰出的环境中为有抱负的独立科学家提供关键培训 宾夕法尼亚州。特别是，这项提议代表着实现申请人职业目标的关键一步 领导自己的实验室，将全面、平衡的培训计划与创新的 调查VTA-GABA神经元兴奋性在青少年尼古丁诱导的成人中的作用的研究计划 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.