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.

项目摘要 靶向μ阿片受体（莫尔）的阿片类药物是广泛有效的疼痛缓解药物，但阿片类药物滥用 在美国达到了创纪录的水平。尽管阿片类药物滥用和依赖程度很高， 对莫尔激动剂暴露如何引起奖赏和成瘾的理解是有限的。总体 这个提议的目的是研究有助于莫尔介导的奖赏的回路。我们将专注于 腹侧被盖区（VTA）与莫尔介导的奖赏之间的联系 （Olmstead和富兰克林，1997; Zhang等人，2009）和外侧缰核（LHb），后者由 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的多巴胺 在阿片依赖性动物中的奖励，在幼稚动物中不需要（Bechara等人，1992年; Nader和货车 der Kooy，1997）。因此，为了了解向阿片类药物依赖和滥用的过渡， 确定介导莫尔奖赏的非多巴胺能VTA输出回路。VTA到LHb的投影 是非多巴胺能的（Root等，2014年），并且是莫尔奖的潜在候选人。由于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 对LHb的投射产生厌恶（Root等人，2014），莫尔抑制VTA谷氨酸投射至 LHB应该是奖励。我们的初步数据显示，莫尔诱导抑制VTA投射。我们 初步数据还显示了对投射到GABA能RMTg的LHb神经元的直接莫尔抑制， 通过解除腹侧被盖区多巴胺神经元的抑制来发出奖励信号。我们将充分描述VTA中的莫尔效应- LHb回路，包括研究莫尔在每个突触部位的作用机制， 通过莫尔激活使LHb神经元的投射靶超极化。联同 电生理学，我们将在记录的神经元中进行32个靶mRNA的单细胞nCounter检测， 能够完全表征由记录的神经元释放（或共同释放）的神经递质， 识别新受体靶点。我们将使用行为药理学和光遗传学来确定 这些回路在幼稚动物和未受损伤的神经损伤模型中对莫尔奖赏的贡献 神经性疼痛，因为疼痛激活LHb并导致不同脑区的莫尔功能改变 包括VTA（例如Hipolito等人，2015年）的报告。鉴于这两个奖励由于缓解慢性疼痛和阿片类药物 阿片依赖动物的奖赏需要多巴胺，我们将探讨莫尔的状态依赖性变化 功能的VTA-LHb电路使用切片电生理学。通过比较mRNA表达， 在这些回路中的单个神经元，在幼稚的，慢性疼痛的和吗啡依赖的动物中，我们将能够 确定转变为阿片类药物依赖的分子和突触变化， 未来药物开发的潜在目标。这项工作将有助于开发更有效的治疗方法。 可以避免阿片类药物耐受性、依赖性和滥用问题的止痛剂。

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