Regulation of striatal microcircuits by endogenous opioids as a novel mechanism underlying cocaine seeking

内源性阿片类药物对纹状体微电路的调节作为可卡因寻求的新机制

基本信息

批准号：
10522905
负责人：
Lauren K Dobbs
金额：
$ 54.36万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
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：
2022-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522905
关键词：
Action Potentials Affect Attenuated Automobile Driving Axon Behavior Cells Cocaine Cocaine Abuse Corpus striatum structure Coupled Cues Data Distal Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Dose Drug usage Dynorphins Electrophysiology (science)Enkephalins Epidemiology Foundations Genotype Globus Pallidus Goals Health Immunohistochemistry Intake Knock-out Knockout Mice Lead Link Long-Term Depression Measures Mediating Messenger RNA Mission Motivation Mus National Institute of Drug Abuse Neurons Opioid Opioid Antagonist Opioid Peptide Opioid agonist Opsin Outcome Output Pathway interactions Peptides Pharmaceutical Preparations Pharmacology Population Procedures Protease Inhibitor Protocols documentation Psychological reinforcement Public Health Receptor Signaling Recording of previous events Regulation Reporting Research Rewards Saline Signal Transduction Slice Source Surveys Synaptic plasticity Testing Training Tweens Western Blotting Work base cocaine exposure cocaine self-administration cocaine use conditioned place preference drug abstinence endogenous opioids gamma-Aminobutyric Acid insight motivated behavior mu opioid receptors neural circuit neuronal excitability novel optogenetics preference response stem transmission process

项目摘要

PROJECT SUMMARY. Recent epidemiological reports indicate that cocaine use increased by 45% from 2013 to 2018. Cocaine-induced increase in striatal dopamine levels is linked to its rewarding effects. However, the striatal neural circuits driving cocaine abuse are not clearly defined. Thus, there is a critical need to delin- eate how the striatal circuits downstream of cocaine-induced dopamine release control cocaine seeking and taking. The overall objective of this proposal is to determine the mechanisms by which cocaine affects GABA transmission between the two principal neurons of the striatum, the D1-MSNs and D2-MSNs, to ultimately regulate drug seeking and taking. Our central hypothesis is that cocaine-enhances levels of the opioid peptide enkephalin, which acts via mu-opioid receptors (MOR) expressed in axon collaterals of D1- and D2-MSNs to facilitate cocaine seeking and taking. We will test this in two specific aims: Aim 1: Determine the mechanisms for how cocaine affects plasticity of intra-striatal GABA trans- mission. Based on our preliminary data, we hypothesize that a history of cocaine increases enkephalin re- lease from D2-MSNs, which induces MOR-dependent long-term depression of intra-striatal GABA transmis- sion onto D1-MSNs. We will test this by performing whole cell electrophysiology in MSN-selective MOR and enkephalin knockouts with a history of cocaine or saline exposure, and record GABA transmission between MSNs and MSN excitability. Pharmacology will be used to infer heightened enkephalin tone in electrophysi- ology recordings, and this will be confirmed by RNAscope, immunohistochemistry, Western blot and our MSN- selective enkephalin knockout. Aim 2: Determine how opioid regulation of intra-striatal circuits drive cocaine seeking and taking. Based on our preliminary data we hypothesize that enkephalin released from D2-MSNs acts on MORs in axon collaterals of D1- and D2-MSNs to suppress intra-striatal GABA and facilitate cocaine reward. We will test this using operant cocaine self-administration procedures in MSN-selective MOR and enkephalin knock- out mice. We will determine how intra-striatal GABA transmission from MSNs contributes to cocaine seeking by selectively inhibiting D1-MSN or D2-MSN striatal axon collaterals using a novel Gi-coupled opsin during a cued cocaine seeking task. Successful completion of the proposed research will elucidate how endogenous opioids regulate intra- striatal GABA transmission, and how cocaine impinges upon this mechanism to affect circuit activity. Moreo- ver, this research will provide novel insights on the mechanisms of cocaine abuse by establishing a link be- tween opioid-mediated regulation of intra-striatal GABA transmission and cocaine seeking and taking. This research will also lay the groundwork for our long-term goal of determining the circuit mechanisms driving synergistic reward when opiates and cocaine are co-abused.

项目摘要。最近的流行病学报告表明，可卡因使用量增加了 45% 2013 年至 2018 年。可卡因引起的纹状体多巴胺水平增加与其奖励效应有关。然而，导致可卡因滥用的纹状体神经回路尚未明确定义。因此，迫切需要消除吃可卡因诱导的多巴胺释放下游纹状体回路如何控制可卡因寻找和服用。该提案的总体目标是确定可卡因影响 GABA 的机制纹状体的两个主要神经元 D1-MSN 和 D2-MSN 之间的传输，最终规范寻求和服用药物。我们的中心假设是可卡因增强阿片肽的水平脑啡肽，通过 D1- 和 D2-MSN 轴突侧支中表达的 mu-阿片受体 (MOR) 发挥作用，促进可卡因的寻找和吸食。我们将在两个具体目标上对此进行测试：目标 1：确定可卡因如何影响纹状体内 GABA 反式可塑性的机制使命。根据我们的初步数据，我们假设可卡因的使用史会增加脑啡肽的水平 D2-MSNs 的租赁，诱导 MOR 依赖性纹状体内 GABA 传输的长期抑制转移到 D1-MSN 上。我们将通过在 MSN 选择性 MOR 中进行全细胞电生理学来测试这一点具有可卡因或盐水接触史的脑啡肽敲除，并记录 GABA 在 MSN 和 MSN 兴奋性。药理学将用于推断电生理学中脑啡肽张力的升高学记录，这将通过 RNAscope、免疫组织化学、Western blot 和我们的 MSN 来证实选择性脑啡肽敲除。目标 2：确定纹状体内回路的阿片类药物调节如何驱动可卡因的寻找和吸食。根据我们的初步数据，我们假设 D2-MSN 释放的脑啡肽作用于 MOR D1-和 D2-MSN 的轴突侧支抑制纹状体内 GABA 并促进可卡因奖赏。我们将使用 MSN 选择性 MOR 和脑啡肽敲击中操作性可卡因自我给药程序对此进行测试出老鼠。我们将确定 MSN 的纹状体内 GABA 传输如何促进可卡因寻找通过使用新型 Gi 耦合视蛋白选择性抑制 D1-MSN 或 D2-MSN 纹状体轴突侧枝提示可卡因寻找任务。成功完成拟议的研究将阐明内源性阿片类药物如何调节体内纹状体 GABA 传输，以及可卡因如何影响该机制以影响电路活动。更多- 事实上，这项研究将通过建立以下联系来提供关于可卡因滥用机制的新颖见解：阿片类药物介导的纹状体内 GABA 传输调节与可卡因寻求和吸食之间的关系。这研究还将为我们确定驱动电路机制的长期目标奠定基础当阿片类药物和可卡因同时滥用时，会产生协同奖励。