Molecular Basis for Structural and Behavioral Effects of Chronic Opioid Exposure

慢性阿片类药物暴露的结构和行为影响的分子基础

基本信息

批准号：
10615802
负责人：
Dieter Brandner
金额：
$ 3.27万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-24 至 2024-06-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10615802
关键词：
3-Dimensional Acute Addictive Behavior Address Affect American Animals Attenuated Behavior Behavioral Brain Diseases Cell Adhesion Molecules Cell Differentiation process Cessation of life Chronic Classification Data Dendritic Spines Dependence Development Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Dose Event Excitatory Synapse Exhibits Exposure to Foundations Future Genetic Goals Individual Inhibitory Synapse Intervention Knock-out Knockout Mice Knowledge Laser Scanning Confocal Microscopy Length Locomotion Measures Mentorship Methods Molecular Monsters Morphine Morphology Motor Activity Mus Mutation Neuronal Plasticity Neurons Nucleus Accumbens Opiate Addiction Opioid Pathway interactions Pattern Pharmaceutical Preparations Phenotype Population Procedures Property Proteins Public Health Recurrent disease Relapse Research Rewards Risk Reduction Role Scaffolding Protein Shapes Site Specificity Stimulus Structure Subcellular structure Synapses Synaptic Transmission Synaptic plasticity Techniques Training Translating Ventral Tegmental Area Vertebral column Virus Visualization addiction behavioral response career cell type conditioned place preference density design and construction dopaminergic neuron drug of abuse drug reinforcement drug reward effective therapy experimental study genetic linkage gephyrin knockout animal morphine administration mortality mutant neural neural correlate neuroligin 3 neuromechanism neuroregulation novel therapeutics opioid exposure postsynaptic preference prevent rational design response synaptic function therapy design

项目摘要

PROJECT SUMMARY Opioid addiction is a chronic relapsing disease affecting at least 2 million Americans with an associated annual mortality approaching 50,000 deaths. Currently available interventions have proven ineffective in addressing this public health crisis. Over the past several decades, significant progress has been made in identifying the neural mechanisms of opioids. Like other drugs of abuse, opioids activate the mesolimbic dopamine pathway, increasing the excitability of dopaminergic neurons in the ventral tegmental area (VTA) and enhancing dopamine neuromodulation via projections to a variety of targets. The effects of mesolimbic dopamine activation in mice are well studied and include heightened locomotor activity. One VTA target, the nucleus accumbens (NAc), is thought to act as a “rheostat” of reward, and fluctuations in dopamine release in this region appear to control whether stimuli are perceived as rewarding or aversive. Beyond acute effects, repeated administration of opioids demonstrates that these drugs are capable not only of modifying dopamine release but also of inducing plasticity in the dopamine response. For example, in a phenomenon known as psychomotor sensitization, repeated exposure to a fixed dose of opioid produces a progressive increase in locomotion. As a neural correlate of sensitization, opioids are known to induce alterations in the density of synaptic contacts onto the dominant neuronal population in the NAc, medium spiny projection neurons (MSNs). These changes likely modify the internal circuit dynamics of the NAc to accentuate drug reward and reinforcement, contributing to the development addiction and relapse. However, a dearth of knowledge concerning opioid-induced changes to the microcircuitry of key neural reward substrates presents a significant barrier to the rational design of therapies aimed at preventing opioid-induced synaptic rewiring. MSNs are heterogenous, consisting of at least two subpopulations, distinguishable by their expression of the D1-dopamine receptor or the D2-dopamine receptor. D1-MSNs appear to promote addictive behaviors while D2-MSNs may oppose these behaviors. Despite the functional significance of these differences, the cell-type specificity of opioid-induced morphologic changes has not been investigated. The proposed experiments will examine subtype-specific structural plasticity of excitatory and inhibitory synapses onto MSNs in the NAc in response to repeated morphine exposure. We will then evaluate the same parameters in a mutant known to exhibit attenuated psychomotor sensitization to determine whether subtype- specific spine changes by this mutation.

项目摘要阿片类药物成瘾是一种慢性传播疾病，影响至少200万美国人年死亡率接近50,000人死亡。当前可用的干预措施已证明无效解决这一公共卫生危机。在过去的几十年中，已经取得了重大进展识别卵动物的神经机制。像其他滥用药物一样，opioids激活了中唇多巴胺途径，增加了腹侧对段区域（VTA）中多巴胺能神经元的兴奋并通过项目对各种目标增强多巴胺神经调节。中唇骨的影响小鼠的多巴胺激活进行了良好的研究，并包括增强的运动活性。一个VTA目标，伏隔核（NAC）被认为充当奖励的“变阻器”，多巴胺释放的波动该区域似乎控制刺激是否被认为是有益的还是厌恶的。超越急性影响，反复给药阿片类药物表明，这些药物不仅能够修饰多巴胺在多巴胺反应中释放但也具有诱导的可塑性。例如，以一种称为心理运动敏感性，反复接触固定剂量的阿片类药物会逐渐增加运动。作为敏感性的神经相关性，已知阿片类药物会影响变化在NAC，中棘投影神经元中的主要神经元种群上的突触接触（MSN）。这些更改可能会改变NAC的内部电路动力学，以强调药物奖励和加强，有助于增强发展和救济。但是，知识死亡有关OioID引起的关键神经奖励基板微电路的变化呈现旨在防止阿片类药物引起的突触的理性设计的重大障碍重新布线。 MSN是异质的，由至少两个亚群组成，可以通过其区分 D1多巴胺受体或D2多巴胺受体的表达。 D1-MSN似乎促进了添加剂虽然D2-MSN可能会反对这些行为。尽管这些功能意义尚未研究差异，阿片类药物诱导的形态变化的细胞类型特异性。这建议的实验将检查运动和抑制突触的亚型特异性结构可塑性响应重复的吗啡暴露，进入NAC中的MSN。然后我们将评估相同的已知暴露于减弱心理运动敏感性的突变体中的参数，以确定亚型是否特定的脊柱因这种突变而变化。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

μ-Opioid Receptor (Oprm1) Copy Number Influences Nucleus Accumbens Microcircuitry and Reciprocal Social Behaviors.

μ-阿片受体 (Oprm1) 拷贝数影响伏核微电路和交互社会行为。

DOI：
10.1523/jneurosci.2440-20.2021
发表时间：
2021
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Toddes,Carlee;Lefevre,EmiliaM;Brandner,DieterD;Zugschwert,Lauryn;Rothwell,PatrickE
通讯作者：
Rothwell,PatrickE