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A patch circuit dissection of opioid addiction

阿片类药物成瘾的补丁电路剖析

基本信息

批准号：
10591745
负责人：
Jason M Tucciarone
金额：
$ 19.27万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591745
关键词：
American Analgesics Axon Behavior Behavioral Biological Assay Brain COVID-19 pandemic Calcium Cells Characteristics Clinical Research Consumption Corpus striatum structure Depressed mood Desire for food Dissection Dopamine Receptor Dorsal Extinction Fiber Foundations Gene Expression Genetic Goals Health Immediate-Early Genes Intervention Intoxication Island Knowledge Label Maintenance Measures Mediator Monitor Naloxone Negative Reinforcements Negative Valence Nervous System Neuroanatomy Neurobiology Neurons Nucleus Accumbens Opiate Addiction Opioid Opioid Receptor Optics Output Pathologic Pathway interactions Pattern Pharmaceutical Preparations Phase Photometry Population Positive Reinforcements Positive Valence Pre-Clinical Model Property Psychological reinforcement Public Health Rabies Relapse Rewards Role Self Administration Source Substance Use Disorder Techniques Training Ventral Striatum Viral Virus Withdrawal Withdrawal Symptom Work addiction behavioral economic analysis cell type combat conditioned place preference drug abstinence drug reward genetic manipulation insight lens medication-assisted treatment motivated behavior mouse genetics mu opioid receptors neuroimaging novel therapeutics opioid abuse opioid epidemic opioid mortality opioid overdose opioid use opioid use disorder opioid withdrawal optogenetics pharmacologic preclinical study prodynorphin receptor expression recruit response striosome

项目摘要

PROJECT SUMMARY/ABSTRACT The opioid crisis remains a major health concern with millions of Americans addicted to opioid drugs and thousands of opioid related deaths per year. The sad reality is that while medication assisted therapies are highly effective, relapse rates remain high. More understanding is needed into the neurobiology and circuits of opioid addiction to identify new therapies. Opioids exert their rewarding and addictive effects through action at the mu opioid receptor (MOR). The MOR is expressed widely throughout the nervous system including regions associated with drug reward such as the nucleus accumbens. It is present in a peculiar neuroanatomic organization referred to as “patch” or “striosome,” with dense regional expression situated in a network of islands throughout dorsal striatum and nucleus accumbens. The region outside of these islands is referred to as matrix. The functional relevance of this level of neuroanatomic organization is mysterious and its consequence for opioid use disorders is almost completely unknown. While the direct and indirect pathway of striatal organization has revealed critical insights into motivated behavior and pathologic changes associated with substance use disorders, it remains incomplete especially in regions of the ventral striatum such as the nucleus accumbens. The neuroanatomy of “patch” vs “matrix,” and the cell types contained within each compartment, opens the possibility for a revived lens through which to look at the functional organization of the nucleus accumbens in motivated behavior and addiction. Recently, the power of mouse genetics revealed two separate populations of direct pathway medium spiny neurons housed within MOR positive patch networks. Further work has shown that while one population encodes positive valence and positive reinforcement, the other encodes negative valence and negative reinforcement, challenging the traditional dogma of the direct pathway. This proposal resubmission begins to define a role for these cell populations in preclinical models of opioid abuse, investigating the properties of patches in the valence of opioids and withdrawal, opioid consumption, maintenance, extinction and reinstatement. Input and output circuitry will be defined in each patch cell type within the nucleus accumbens. The work will combine opioid self-administration, behavioral economic analysis, viral neuroanatomic techniques, optogenetic and chemogenetic manipulations and cell type neuroimaging with fiber photometry. This work will be among the first to study MOR (+) patch circuits in the context of opioid use disorder. Through this new lens of functional organization, insights can be revealed that could lead to new therapies in treating the devastating health and societal impact of opioid use disorders.

项目总结/文摘