Ventral Tegmental Area GABA Neurons: Plasticity & Opiate Receptors at Inhibitory Inputs

腹侧被盖区 GABA 神经元：可塑性

• 批准号: 10046693
• 负责人: JEFFREY G EDWARDS
• 金额: $ 45万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046693
• 关键词: Address; Alcohol abuse; Alcohols; Behavior; Behavioral Mechanisms; Brain; Brain region; Cause of Death; Cell physiology; Cells; Complex; Data; Dependence; Disease; Dopamine; Drug abuse; Electrophysiology (science); Epidemic; Exhibits; Genetic Models; Goals; Government; Illicit Drugs; Individual; Lead; Location; Measures; Mediating; Mission; Modification; Molecular Biology; Morphine; Motivation; National Institute of Drug Abuse; Neurobiology; Neurons; Opiate Addiction; Opioid; Opioid Receptor; Paint; Pathway interactions; Perception; Pharmaceutical Preparations; Pharmacology; Physiology; Relapse; Reporting; Research; Rewards; Role; Site; Smoking; Specificity; Surveys; Synapses; Synaptic plasticity; System; United States National Institutes of Health; United States Substance Abuse and Mental Health Services Administration; Ventral Tegmental Area; Vision; addiction; base; classical conditioning; combat; cost; dopaminergic neuron; drug of abuse; experience; gamma-Aminobutyric Acid; in vivo; innovation; mouse model; neural circuit; neuroadaptation; neurobiological mechanism; new therapeutic target; novel; opioid abuse; opioid epidemic; optogenetics; substance abuse treatment; synthetic opioid; treatment program; treatment strategy; web site

Over 22 million people need treatment for illicit drug/alcohol abuse in the U.S. (SAMHSA survey), costing the government $468 billion per year in related expenses. After alcohol and smoking, opiates are the leading cause for those admitted to substance abuse treatment programs. Currently, there is an opiate crisis throughout the US. Opiate abuse resulted in an exponential increase in synthetic opiate-caused deaths from ~3,000 in 2012 to almost 30,000 in 2017 (NIDA website: Aug. 2018). However, individuals attempting to overcome opiate as well as other addictions often relapse. Therefore, a better understanding of the reward circuit, in addition to a complete understanding of opiate targets in the reward circuit is essential. Here we propose to investigate a novel form of synaptic plasticity of inhibitory inputs onto inhibitory GABA cells in the ventral tegmental area (VTA), the brain's reward center. Within the VTA, dopamine-containing cells are involved in motivation and reward. Reward is an essential component of survival, mediated by increased dopamine release from the VTA. Drugs of abuse dramatically enhance dopamine levels beyond normal rewarding behaviors, and cause synaptic modifications on VTA cells, leading to the diseased state of addiction. While known that illicit drugs cause modifications dopamine cell synapses, neither normal synaptic plasticity of GABA neurons nor how opiates alter GABA neuron activity is completely known. This, despite the fact that GABA neurons are involved in vivo in both the perception and associative learning of reward. Therefore, this role in reward makes VTA GABA cells nearly as important as DA cells to understand. As opiates mediate non-pain related actions in the VTA, our findings will paint a clearer picture of neurocircuit adaptations caused by opiates and provide a base for examining the effect of other drugs of abuse on GABA plasticity. The long-term goal is to understand normal physiology and opiate modification of inputs to VTA GABA cells. We hope by examining more fully opiate-induced neuroadaptations in the VTA, it will provide better, more comprehensive solutions to reverse addiction. We hypothesize that inhibitory inputs to VTA GABA cells undergo novel forms of synaptic plasticity and that opiates will alter these synaptic inputs and thus GABA cell activity. We will examine this hypothesis using single cell electrophysiology, optogenetics, and molecular biology. We anticipate VTA GABA cells will exhibit two forms of plasticity and opiates will alter their activity. We will employ optogenetics to activate specific circuits independently thus determining which circuit correlates to each plasticity type and the location of opiate receptors. As currently there are no good treatments to address opiate or other addictions, the identification of a novel target for drugs of abuse could lead to potential new avenues of treatment.

在美国，超过2200万人需要治疗非法药物/酒精滥用（SAMHSA调查）， 政府每年的有关开支为4，680亿元。在酒精和吸烟之后，阿片类药物是 这是那些接受药物滥用治疗计划的人的主要原因。目前有一种鸦片制剂 整个美国的危机。阿片类药物滥用导致合成阿片类药物引起的 死亡人数从2012年的约3，000人增加到2017年的近30，000人（NIDA网站：2018年8月）。然而，个人 试图克服鸦片以及其他成瘾往往复发。因此，更好地理解 奖励电路，除了在奖励电路阿片类药物的目标是一个完整的理解是 具有本质意义在这里，我们提出了一种新的形式的突触可塑性的抑制性输入， 抑制GABA细胞在腹侧被盖区（VTA），大脑的奖励中心。在VTA内部， 含多巴胺的细胞参与动机和奖励。奖励是一个重要组成部分， 存活，介导的增加多巴胺释放从腹侧被盖区。滥用药物大大增加了 多巴胺水平超过正常的奖励行为，并导致VTA细胞的突触修饰， 导致成瘾的病态虽然已知非法药物会导致多巴胺细胞的改变， 突触，既不是正常的GABA神经元的突触可塑性，也不是阿片类药物如何改变GABA神经元的活动 是完全已知的。尽管GABA神经元在体内参与了感知， 和奖励的联想学习。因此，这种奖励作用使得腹侧被盖区GABA细胞几乎同样重要， as DA DA细胞to understand理解.由于阿片类药物介导腹侧被盖区的非疼痛相关行为，我们的研究结果将描绘一个 更清楚地了解阿片类药物引起的神经回路适应，并为检查其影响提供基础。 对GABA可塑性的影响。长期目标是了解正常的生理学， 对VTA GABA细胞输入的阿片修饰。我们希望通过更全面地检查阿片类药物引起的 通过腹侧被盖区的神经适应，它将提供更好、更全面的解决方案来扭转成瘾。我们 假设对VTA GABA细胞的抑制性输入经历了新形式的突触可塑性， 阿片类药物将改变这些突触输入并因此改变GABA细胞活性。我们将使用单个 细胞电生理学、光遗传学和分子生物学。我们预计腹侧被盖区GABA细胞将表现出两个 可塑性和阿片类药物的形式会改变它们的活性。我们将利用光遗传学来激活特定的电路 从而独立地确定哪个回路与每种可塑性类型和阿片剂的位置相关 受体。由于目前没有很好的治疗方法来解决阿片类药物或其他成瘾， 滥用药物的新靶点可能会导致潜在的新治疗途径。