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

青少年尼古丁诱导的成人吗啡奖赏增强：中脑抑制回路的介导

基本信息

批准号：
10457248
负责人：
Ruthie Wittenberg
金额：
$ 3.41万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457248
关键词：
Action Potentials Address Adolescence Adolescent Adult Affect Automobile Driving Behavior Behavioral Biological Assay Brain Cell Nucleus Cells Cessation of life Clinical Data Development Dopamine Drug Addiction Drug abuse Drug usage Elderly Electrophysiology (science)Elements Environment Future Genetic Goals Grant Human Injections Intervention Laboratories Learning Life Link Literature Locomotion Mediation Mediator of activation protein Membrane Midbrain structure Morbidity - disease rate Morphine Morphine Abuse Motivation Mus Neurobiology Neurons Nicotine Opioid Pathologic Pennsylvania Pharmaceutical Preparations Pharmacology Physiologic pulse Physiology Population Property Psychological reinforcement Public Health Research Research Personnel Rewards Risk Risk Factors Rodent Model Role Scientist Signal Transduction Source Structure Synapses Synaptic Transmission Testing Training United States Universities Vaporizer Ventral Tegmental Area Viral Viral Vector Work abuse liability behavior measurement behavioral pharmacology behavioral response career conditioned place preference dopaminergic neuron drug reinforcement drug reward electronic cigarette use epidemiology study experience experimental study gamma-Aminobutyric Acid in vivo innovation insight mortality neuroadaptation nicotine exposure nicotine treatment nicotine use novel novel therapeutic intervention opioid abuse opioid epidemic opioid use patch clamp postsynaptic preference preventable death programs relating to nervous system response reward processing skills standard measure tobacco products transmission process

项目摘要

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.

项目概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。导致这一严重公共卫生问题的因素之一是先前使用尼古丁是一个重要但效果不佳的因素了解尼古丁是烟草制品（包括电子产品）的主要成瘾成分。尽管人类流行病学令人信服，但吸烟在青少年中尤其普遍3。研究将青少年尼古丁使用与未来阿片类药物滥用联系起来4，潜在的大脑机制仍然存在为了解决这一科学差距，该提案调查了联系的神经生物学基础。青少年尼古丁使用与成人阿片类药物滥用与文献5一致，我们的试点行为数据。证明在青春期接受尼古丁治疗的小鼠对吗啡配对表现出更强的偏好条件性位置偏好（CPP）范式中的背景作为这种行为的潜在神经基础。相互作用，腹侧被盖区（VTA）是一个异质中脑核，由多巴胺和和 GABA 神经元，这对于奖励处理和药物相关行为至关重要 6-9。文献中，丹尼实验室之前的工作表明，青少年时期接触尼古丁发育窗口导致 VTA GABA 神经元功能发生持续变化，从而驱动药物增强作为这种尼古丁诱导的 VTA 神经适应的证据，我们的试点电生理学结果显示，吗啡对 VTA GABA 神经元的药理作用（即抑制）是青少年尼古丁治疗如何改变 GABA 神经元功能？与吗啡奖励的相关性仍然未知。由于这些原因，该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为了检验这个假设，我提出的项目整合了离体电生理学和体内化学遗传学。操作和行为药理学来探究 VTA GABA 神经元兴奋性在具体来说，目标 1 描述了青少年尼古丁诱导的大气吗啡奖励的效果。青少年尼古丁对吗啡诱导的 VTA 中抑制信号传导的决定作用。青少年尼古丁暴露引起的 VTA GABA 神经元活动，驱动哮喘吗啡 CPP。总的来说，这项工作的结果将深入了解尼古丁引起的吗啡滥用的神经基础责任并将进一步加深我们对药物奖励处理中脑可塑性的理解。还在大学优越的环境中为有抱负的独立科学家提供重要的培训特别是，该提案代表了实现申请人职业目标的关键一步。通过将全面、均衡的培训计划与创新的技术相结合来领导自己的实验室研究计划调查 VTA GABA 神经元兴奋性在青少年尼古丁诱导的成人中的作用阿片类药物滥用。