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复发疾病，影响至少200万美国人每年接近50,000人死亡的荒芜。解决这一公共卫生危机。鉴定阿片类药物的神经机制。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性并通过对各种目标的投影增强多巴胺神经调节。对小鼠的多巴胺激活进行了充分的研究，并包括一个VTA靶标。伏隔核（NAC）被刺激为奖励的“变阻器”，在多巴胺释放中波动该区域似乎控制刺激是否被认为是有益的或厌恶的。反复给药阿片类药物表明这些药物不仅能够修饰多巴胺释放，但也诱导多巴胺反应中的塑料。心理运动敏化，反复接触固定剂量的剂量会产生逐步增加运动。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）。强化，有助于发展和复发。关于阿片类药物引起的关键神经奖励底物微电路的变化提出了A 家庭理性设计的重大障碍。重新布线。 D1多巴胺受体或D2多巴胺受体的表达似乎促进了上瘾的尽管有功能，但D2-MSN的行为可能会反对这些。差异，阿片类药物诱导的形态变化的细胞类型特异性尚未研究支撑的实验将检查亚型特异性结构塑料塑料，不可自然的突触在呼吸的吗啡暴露中的NAC中的MSN。已知突变体的参数表现出衰减的心理敏感性敏感性，是否subtype- 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