Opioid Sensitive GABA inputs to the Ventral Midbrain

阿片类药物敏感 GABA 输入至腹侧中脑

• 批准号: 8388483
• 负责人: JOHN T WILLIAMS
• 金额: $ 22.67万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8388483
• 关键词: Afferent Pathways; Aftercare; Agonist; Anhedonia; Animals; Area; Behavioral; Brain; Cell Nucleus; Cells; Chronic; Complex; Corpus striatum structure; Development; Disinhibition; Dopamine; Globus Pallidus; Goals; Halorhodopsins; Interneurons; Knowledge; Light; Maintenance; Measures; Mediating; Midbrain structure; Morphine; Neurons; Nucleus Accumbens; Opioid; Opioid Receptor; Pathway interactions; Pattern; Peripheral Nervous System; Play; Process; Property; Protocols documentation; Rattus; Recruitment Activity; Relative (related person); Rest; Rewards; Role; Site; Slice; Source; Substantia nigra structure; System; Tail; Time; Withdrawal; addiction; dopamine system; dopaminergic neuron; drug of abuse; gamma-Aminobutyric Acid; mesolimbic system; mu opioid receptors; optogenetics; protocol development; research study; tool

DESCRIPTION (provided by applicant): Mu-opioid receptors are widely distributed in the central and peripheral nervous systems. The action of opioids in the mesolimbic dopamine pathway activates the reward pathway(s) that are a key point in the multistep process leading to abuse and addiction. Opioid receptors are expressed in multiple parts of the mesolimbic system and the action of opioids in one area of this complex system may contribute to, but will surely not dominate all aspects of the rewarding properties of opioids. For the past 20 years the action of opioids in the ventral midbrain dopamine system rested on the GABA interneurons of the VTA. Inhibition of those interneurons was proposed to increase the activity of dopamine neurons through a disinhibition. It is now clear that the action of opioids in the ventral midbrain is more complex. There are a number of GABA neurons that innervate dopamine neurons and many of those neurons express opioid receptors. Each of these afferent pathways can now be manipulated selectively with the use of optogenetic tools such that a comprehensive picture of opioid action can be obtained. This proposal will identify the opioid sensitive GABA inputs to dopamine neurons in naive and morphine treated animals. In order for disinhibition to be functionally relevant, there has to be a substantial amount of inhibition initially. The hypothesisis that the source of inhibition is dependent on the state of the animal. Each inhibitory pathway will be recruited differentially depending on the behavioral state of the animal. The proposed experiments will use brain slice experiments to demonstrate that the relative role of different GABA afferent pathways changes during withdrawal from chronic treatment of animals with morphine. Knowledge that different afferent pathways mediate reward and withdrawal will allow a directed approach to limit both reward and withdrawal. PUBLIC HEALTH RELEVANCE: Opioids activate the mesolimbic reward pathway at multiple sites. The inhibition of GABA inputs to dopamine neurons is one important site of opioid action(s). This study will use selective activation of GABA inputs in slices from naive and morphine treated animals to determine which GABA pathway dominates inhibition of dopamine neurons. Knowledge of the inhibitory control of dopamine neurons will facilitate the development of protocols that will reduce the abuse liability of opioids.

描述(申请人提供)：Mu-阿片受体广泛分布于中枢和外周神经系统。阿片类药物在中脑边缘多巴胺通路中的作用激活了奖励通路(S)，这是导致滥用和成瘾的多步骤过程中的一个关键点。阿片受体在中脑边缘系统的多个部分表达，阿片类药物在这个复杂系统的一个区域的作用可能有助于，但肯定不会主宰阿片类药物奖励特性的所有方面。在过去的20年里，阿片类药物在腹侧中脑多巴胺系统中的作用依赖于VTA的GABA中间神经元。抑制这些中间神经元被认为是通过去抑制来增加多巴胺神经元的活性。现在清楚的是，阿片类药物在腹侧中脑的作用更多 很复杂。有许多GABA神经元支配多巴胺神经元，其中许多神经元表达阿片受体。现在可以利用光遗传工具选择性地操纵这些传入通路中的每一条，以便获得阿片类药物作用的全面图像。这项建议将确定在幼稚和吗啡处理的动物中，对阿片类药物敏感的GABA输入到多巴胺神经元。为了使去抑制具有功能相关性，最初必须有大量的抑制。抑制源取决于动物状态的假说。每条抑制途径都会 根据动物的行为状态不同地招募。拟议的实验将使用脑片实验来证明不同的GABA传入通路在戒断吗啡慢性治疗动物过程中的相对作用发生变化。知道不同的传入通路调节奖赏和撤退将允许一种定向的方法来限制奖赏和撤退。 与公共健康相关：阿片类药物在多个部位激活中脑边缘奖赏通路。抑制GABA对多巴胺神经元的传入是阿片类药物作用的一个重要部位(S)。这项研究将使用选择性激活来自幼稚和吗啡处理的动物脑片中的GABA输入来确定哪个GABA途径主导对多巴胺神经元的抑制。了解对多巴胺神经元的抑制控制将有助于制定减少阿片类药物滥用倾向的方案。