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：
10156205
负责人：
Ruthie Wittenberg
金额：
$ 4.6万
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/10156205
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 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。许多元素助长了这个严重的公共卫生问题，事先使用尼古丁是一个重要但很差的了解风险因素2。尼古丁是烟草产品的主要添加剂成分，包括电子青少年中尤其普遍存在的香烟3。尽管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4，潜在的大脑机制仍然存在不清楚。为了解决这一科学差距，该提案研究了链接的神经生物学基础青少年尼古丁与成人阿片类药物滥用一起使用。与文献一致，我们的飞行员行为数据证明青少年中用尼古丁治疗的小鼠表现出对吗啡对的偏好增强条件地点偏好（CPP）范式中的上下文。作为这种行为的潜在神经底物相互作用，腹侧盖区（VTA）是一种异质的中脑核，由两种多巴胺组成和GABA神经元，这对于奖励加工和与药物有关的行为至关重要。6-9。扩展此文献，Dani实验室的先前工作表明，青少年期间的尼古丁暴露发育窗口会产生VTA GABA神经元功能的持续变化，该功能驱动增强的药物寻求10。作为VTA中这种尼古丁诱导的神经适应的证据，我们的飞行员电生理学结果表明，吗啡对VTA GABA神经元的药物作用（即抑制）是通过青春期尼古丁治疗的矛盾倒置（即兴奋）。 GABA神经元功能的变化如何与吗啡奖励相关仍然未知。由于这些原因，该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的激动而促进成人吗啡奖励神经元。为了检验这一假设，我提出的项目整合了体内电生理学，体内化学发生操纵和行为药理学，以审问VTA GABA神经元在青春期尼古丁引起的吗啡奖励增强。具体而言，AIM 1表征了关于吗啡诱导的VTA抑制性信号的青春期尼古丁。目标2确定异常的作用 VTA GABA神经元活性是由青春期尼古丁暴露引起的，在推动增强的吗啡CPP时。总的来说，这项工作的结果将为尼古丁引起的吗啡滥用的神经基础提供见识责任，将进一步了解我们对药物奖励处理中的中脑可塑性的理解。这笔赠款将还为大学杰出环境中有抱负的独立科学家提供关键的培训宾夕法尼亚州。特别是，该提案代表了参加申请人的职业目标的关键步骤通过将全面，均衡的培训计划与创新性相结合，领导自己的实验室研究计划旨在研究VTA GABA神经元在青春期诱导的成年人中令人兴奋的作用 OOPIEAD滥用。