The role of the VTA-lateral habenula circuit in opioid mediated behaviors

VTA-外侧缰核回路在阿片类药物介导的行为中的作用

• 批准号: 10198878
• 负责人: Elyssa Margolis
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198878
• 关键词: Analgesics; Animals; Back; Behavior; Brain; Brain region; Cell Nucleus; Cells; Data; Dependence; Detection; Development; Dopamine; Dorsal; Dose; Electrophysiology (science); Elements; Emotional; Exposure to; Future; Glutamates; Grant; Habenula; Human; Individual; Label; Lateral; Measures; Mediating; Messenger RNA; Modeling; Molecular; Morphine; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid agonist; Output; Pain; Pain management; Pain-Free; Pathway interactions; Persistent pain; Pharmaceutical Preparations; Pharmacotherapy; Plant Roots; Rattus; Receptor Activation; Receptor Inhibition; Rewards; Rodent; Role; Signal Transduction; Site; Slice; Stimulus; Structure; Synapses; Synaptic Receptors; Techniques; Tegmentum Mesencephali; Testing; Therapeutic Agents; United States; Ventral Striatum; Ventral Tegmental Area; Work; addiction; balance testing; behavioral pharmacology; chronic pain; chronic pain relief; clinical practice; dopaminergic neuron; drug development; experience; gamma-Aminobutyric Acid; mRNA Expression; mu opioid receptors; nerve injury; neurotransmitter release; novel; opiate tolerance; opioid abuse; opioid exposure; optogenetics; pain processing; pain relief; painful neuropathy; postsynaptic; preference; receptor; receptor function; response; spared nerve; therapeutically effective

PROJECT SUMMARY Opiates targeting the mu opioid receptor (MOR) are broadly effective pain relieving drugs, but opiate abuse is at record levels in the United States. In spite of the magnitude of opiate abuse and dependence, our understanding of how MOR agonist exposure causes reward and addiction is limited. The overarching objective of this proposal is to investigate the circuits that contribute to MOR mediated reward. We will focus on the connections between the ventral tegmental area (VTA) which is required for MOR mediated reward (Olmstead and Franklin, 1997; Zhang et al., 2009), and the lateral habenula (LHb), which is activated by a range of aversive states including pain. Although dopamine in the ventral striatum is required for morphine reward in opiate dependent animals, it is not required in naïve animals (Bechara et al., 1992; Nader and van der Kooy, 1997). Therefore to understand the transition to opioid dependence and abuse it is essential to determine the non-dopaminergic VTA output circuit that mediates MOR reward. The VTA projection to the LHb is non-dopaminergic (Root et al., 2014) and is a potential candidate for MOR reward. Since LHb neurons are activated by painful stimuli (Benabid and Jeaugey, 1989; Zhang et al., 2013) and stimulating VTA glutamate projections to LHb produces aversion (Root et al., 2014), MOR inhibition of VTA glutamate projections to the LHb should be rewarding. Our preliminary data show MOR induced inhibition of this VTA projection. Our preliminary data also show direct MOR inhibitions of LHb neurons that project to the GABAergic RMTg, which signals reward by disinhibiting VTA dopamine neurons. We will fully characterize the MOR effects in the VTA- LHb circuits, including studying the mechanisms of MOR action at each synaptic site and determining the projection target(s) of the LHb neurons hyperpolarized by MOR activation. In conjunction with the electrophysiology, we will perform single cell nCounter detection of 32 target mRNAs in recorded neurons to enable full characterization of the neurotransmitters released (or co-released) by the recorded neurons and to identify novel receptor targets. We will use behavioral pharmacology and optogenetics to determine the contribution of these circuits to MOR reward in both naïve animals and in the spared nerve injury model of neuropathic pain, since pain activates the LHb and leads to changes MOR function in various brain regions including the VTA (e.g. Hipolito et al., 2015). Given that both reward due to relief of chronic pain and opioid reward in opioid dependent animals require dopamine, we will probe the state dependent changes in MOR function in the VTA-LHb circuits using slice electrophysiology. Through comparing mRNA expression in the individual neurons in these circuits in naïve, chronic pain, and morphine dependent animals, we will be able to determine the molecular and synaptic changes that underlie the transition to opioid dependence and identify potential targets for future drug development. This work will enable development of more effective therapeutic agents for pain that can circumvent the problems of opioid tolerance, dependence and abuse.

项目总结 针对Mu阿片受体(MOR)的阿片类药物是广泛有效的止痛药，但阿片类药物滥用 在美国处于创纪录的水平。尽管鸦片类药物滥用和依赖的规模很大，但我们的 对于MOR激动剂是如何导致奖赏和成瘾的理解是有限的。最重要的是 这项建议的目的是研究参与MOR介导的奖赏的回路。我们将重点关注 MOR介导的奖赏所需的腹侧被盖区之间的联系 (Olmstead和Franklin，1997；Zhang等，2009)和外侧缰核(LHb)，它由一种 包括疼痛在内的一系列厌恶状态。尽管吗啡需要腹侧纹状体中的多巴胺 在阿片依赖的动物中，天真的动物不需要奖励(Bechara等人，1992；Nader和Van Der Kooy，1997)。因此，为了理解向阿片依赖和滥用的转变，必须 确定介导MOR奖赏的非多巴胺能VTA输出回路。向LHb的VTA投影 是非多巴胺能的(Root等人，2014)，是MOR奖励的潜在候选者。因为LHb神经元是 由疼痛刺激激活(Benabid和Jeaugey，1989；Zhang等，2013)和刺激VTA谷氨酸 投射到LHb产生厌恶(Root等人，2014)，MOR抑制VTA谷氨酸投射到 LHB应该是有回报的。我们的初步数据显示，MOR诱导了这种VTA投射的抑制。我们的 初步数据还显示，LHb神经元投射到GABA能RMTg的直接MOR抑制，这是 通过抑制VTA多巴胺神经元发出奖赏信号。我们将充分描述VTA中的MOR效应- LHB回路，包括研究MOR在每个突触部位的作用机制，并确定 MOR激活LHb神经元超极化的投射靶点(S)。与 电生理学，我们将对记录的神经元中的32个靶mRNAs进行单细胞计数器检测，以 能够充分表征由记录的神经元释放(或共同释放)的神经递质，并 识别新的受体靶点。我们将使用行为药理学和光遗传学来确定 在幼稚动物和大鼠备用神经损伤模型中这些环路对MOR奖赏的贡献 神经病理性疼痛，因为疼痛激活LHb并导致不同脑区MOR功能的变化 包括VTA(如Hipolito等人，2015年)。考虑到缓解慢性疼痛和阿片类药物的回报 阿片依赖动物的奖赏需要多巴胺，我们将探讨MOR状态依赖的变化 在VTA-LHb电路中使用切片电生理学的功能。通过比较不同细胞系中mRNA的表达 在幼稚、慢性疼痛和吗啡依赖的动物中，这些回路中的单个神经元，我们将能够 确定导致阿片依赖转变的分子和突触变化，并确定 未来药物开发的潜在目标。这项工作将使开发出更有效的治疗方法 止痛药可以绕过阿片类药物耐受、依赖和滥用的问题。

项目成果

Ventral tegmental area GABA, glutamate, and glutamate-GABA neurons are heterogeneous in their electrophysiological and pharmacological properties.

• DOI: 10.1111/ejn.15156
• 发表时间: 2021-02-22
• 期刊: The European journal of neuroscience
• 作者: Miranda-Barrientos J;Chambers I;Mongia S;Liu B;Wang HL;Mateo-Semidey GE;Margolis EB;Zhang S;Morales M
• 通讯作者: Morales M