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The contribution of the hippocampus to learned opiate tolerance

海马体对习得阿片耐受性的贡献

基本信息

批准号：
10586097
负责人：
Brian J Wiltgen
金额：
$ 19.43万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10586097
关键词：
Absence of pain sensation Affect Amygdaloid structure Analgesics Animals Area Association Learning Attenuated Behavioral Biological Assay Brain Cells Chronic Clinical Cocaine Cues Dangerousness Data Dependence Development Dose Environment Exhibits FOS gene Goals Hippocampus Infusion procedures Label Learning Light Mediating Memory Methadone Methods Modernization Morphine Mus Neurons Neurosciences Nucleus Accumbens Opioid Opioid Receptor Opioid agonist Opsin Overdose Pain Pharmaceutical Preparations Pharmacodynamics Play Proteins Reporter Reporter Genes Research Role Signal Pathway Specificity Techniques Testing Training Transgenic Organisms United States Viral Vector Virus Work addiction clinically relevant conditioned fear cost estimate desensitization drug abuse prevention drug efficacy experimental study fear memory memory retrieval morphine tolerance neural circuit novel opiate tolerance opioid use optogenetics pain inhibition pain sensitivity prevent receptor recycling response side effect spatial memory synthetic opioid tool

项目摘要

Project Summary The utility of opiates for treating pain is limited by the development of tolerance, a phenomenon that can lead to dose- escalation and an increased liability for dangerous side effects like dependence and overdose. Interestingly, environmental cues that are paired with opiates can dramatically influence tolerance. Specifically, animals that receive morphine in a particular context exhibit analgesic tolerance that can be eliminated by simply administering the drug in a new environment. The cellular and circuit mechanisms underlying this associative form of tolerance have not been well characterized. However, they are highly relevant clinically as many overdoses occur when addicts take large amounts of opiates in a new place. In this application, we propose to dissect the circuitry underlying associate morphine tolerance using modern behavioral neuroscience tools. Specifically, we will combine optogenetic techniques with transgenic reporter mice to identify the specific neural circuits and cells that mediate associative tolerance. Our central hypothesis is that context-specific representations in the hippocampus become associated with opiate use and produce a compensatory response in the amygdala that prevents the inhibition of pain. To test this idea, we will express light sensitive opsins in the specific neurons that are active during the expression of associative morphine tolerance. We predict that silencing these cells will prevent tolerance in a morphine-paired context. Stimulating these cells, in contrast, should induce tolerance in a novel environment that has never been paired with morphine. A similar strategy has been used to identify and manipulate neurons that encode fear memories in the amygdala, spatial memories in the hippocampus, cocaine memories in the nucleus accumbens and many others forms of memory. However, to our knowledge, this approach has never been applied to associative morphine tolerance. We believe that doing so will lead to significant advances like it has for other forms of learning and memory.

项目摘要阿片类药物治疗疼痛的效用受到耐受性发展的限制，这种现象可能导致剂量- 升级和增加对危险副作用的责任，如依赖和过量用药。有趣的是，与鸦片类药物配对的环境线索可以极大地影响耐受性。具体地说，接受在特定情况下，吗啡表现出止痛耐受性，这种耐受性可以通过简单地在新环境。这种联合形式的耐受背后的细胞和电路机制还不是很好。特色化的。然而，它们在临床上具有很高的相关性，因为许多药物过量发生在吸毒者服用大量在一个新的地方吃鸦片。在这一应用中，我们建议剖析与吗啡耐受相关的回路使用现代行为神经科学工具。具体地说，我们将把光遗传技术与转基因技术结合起来报告小鼠，以确定介导联想耐受的特定神经回路和细胞。我们的中心假设海马体中的上下文特定表征与阿片类药物的使用相关，并产生杏仁核中防止疼痛抑制的代偿反应。为了测试这一想法，我们将表达光在联合吗啡耐受表达过程中激活的特定神经元中的敏感视蛋白。我们可以预见，在吗啡配对的情况下，沉默这些细胞将阻止耐受性。相比之下，刺激这些细胞，应该会在一个从未与吗啡配对的新环境中诱导耐受性。一种类似的策略一直是用来识别和操纵杏仁核中编码恐惧记忆的神经元，空间记忆中的海马体、伏隔核中的可卡因记忆和许多其他形式的记忆。然而，对于我们的据了解，这种方法从未被应用于联合吗啡耐受。我们相信，这样做将导致在其他形式的学习和记忆方面也取得了重大进展。