Relevance and plasticity of inhibitory metabotropic signaling in reward circuits

奖赏回路中抑制性代谢信号的相关性和可塑性

基本信息

批准号：
8609434
负责人：
KEVIN D WICKMAN
金额：
$ 33.53万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8609434
关键词：
Abstinence Acute Address Agonist Anatomy Behavior Behavior assessment Behavioral Brain Brain region Chronic Cocaine Crime Data Development Disease Dopamine Dopamine Receptor Drug Addiction Drug abuse Electrophysiology (science)GTP-Binding Proteins Genetic Glutamates Goals Health Label Lead Link Medial Mediating Molecular Motor Activity Mutant Strains Mice National Institute of Drug Abuse Neurobiology Neurons Neurosciences Research Nucleus Accumbens Output Pharmaceutical Preparations Pharmacology Population Prefrontal Cortex Prevention Process Productivity Progressive Disease Public Health RNA Interference Reagent Relapse Research Research Priority Rewards Role Signal Pathway Signal Transduction Signaling Pathway Gene Slice Source Specificity System Testing Therapeutic United States Ventral Tegmental Area Viral Work addiction base cocaine exposure combat cost craving design dopaminergic neuron drug of abuse drug reward drug seeking behavior hippocampal pyramidal neuron improved in vivo insight interdisciplinary approach neuroadaptation neurochemistry neurotransmission novel prevent public health relevance research study reward circuitry therapy design

项目摘要

DESCRIPTION (provided by applicant): Drug addiction is a progressive disorder characterized by compulsive drug-taking behavior and high rates of relapse, even after prolonged periods of abstinence. The costs associated with drug addiction, factoring in lost productivity, health problems, and crime, are estimated at $600 billion per year in the United States alone. Our limited understanding of the neurochemical, molecular, and cellular mechanisms underlying drug reward, craving, and relapse has impeded our ability to confront this major public health issue effectively. The premise of this proposal is that a better understanding of the signaling pathways that mediate the cellular and behavioral effects of drugs of abuse will improve our ability to combat addiction. The focus of this proposal is on a form of inhibitory signaling and its relevance to the cellular and behavioral effects of acute and repeated cocaine exposure. Our work over the last decade has revealed that the behavioral effects of many drugs of abuse, including cocaine, are dependent on G protein-gated inwardly-rectifying K+ (Girk/KIR3) channels. More recently, we have found that in vivo cocaine exposure suppresses Girk signaling in dopamine (DA) neurons of the ventral tegmental area (VTA) and glutamatergic output neurons of the medial prefrontal cortex (Layer 5/6 mPFC pyramidal neurons), neuron populations instrumental to the reward-related behavioral effects of acute and repeated cocaine exposure. The goals of this project are to understand how cocaine suppresses Girk signaling in VTA DA and Layer 5/6 mPFC pyramidal neurons, and how these adaptations influence reward- related behavior and excitatory neurotransmission in the mesocorticolimbic reward circuitry. The novel conceptual framework is that Girk signaling in VTA DA and Layer 5/6 mPFC pyramidal neurons is an early "addiction barrier" that is overcome by cocaine exposure, paving the way for enduring adaptations linked to craving and relapse. Proposed studies will combine slice electrophysiological and behavioral assessments, with both approaches utilizing a novel array of mutant mouse lines and exploiting recent progress in our ability to perturb Girk signaling with unprecedented molecular, anatomic, and temporal precision. Efforts will center on three specific aims: 1) To understand the acute cocaine-induced suppression of Girk signaling in VTA DA neurons, 2) To understand the repeated cocaine-induced suppression of Girk signaling in mPFC pyramidal neurons, and 3) To probe the relevance of Girk signaling in the VTA and mPFC to reward-related behavior. Successful completion of this project will yield novel insights into the relevance of Girk signaling to reward related behavior, while also highlighting the role of such signaling in the cocaine-induced neuroadaptations that underlie key facets of addiction, including craving and relapse. Accordingly, this project targets multiple strategic goals of the National Institute on Drug Abuse, including prevention and treatment objectives that hinge on expanding our understanding of basic neurobiology as it relates to circuitry underlying addiction.

描述（由申请人提供）：药物成瘾是一种进行性疾病，其特征是强迫性吸毒行为和高复发率，即使在长期戒毒后也是如此。考虑到生产力损失、健康问题和犯罪，仅在美国每年与吸毒成瘾相关的成本估计就达 6000 亿美元。我们对药物奖励、渴望和复发背后的神经化学、分子和细胞机制的了解有限，这阻碍了我们有效应对这一重大公共卫生问题的能力。该提案的前提是更好地了解介导滥用药物的细胞和行为影响的信号通路将提高我们对抗成瘾的能力。该提案的重点是抑制信号传导的一种形式及其与急性和反复接触可卡因的细胞和行为影响的相关性。我们过去十年的工作表明，包括可卡因在内的许多滥用药物的行为影响依赖于 G 蛋白门控内向整流 K+ (Girk/KIR3) 通道。最近，我们发现体内可卡因暴露会抑制腹侧被盖区 (VTA) 的多巴胺 (DA) 神经元和内侧前额叶皮质的谷氨酸输出神经元（第 5/6 层 mPFC 锥体神经元）中的 Girk 信号传导，神经元群体发挥作用急性和反复接触可卡因对奖励相关的行为影响。该项目的目标是了解可卡因如何抑制 VTA DA 和第 5/6 层 mPFC 锥体神经元中的 Girk 信号传导，以及这些适应如何影响中皮质边缘奖励回路中的奖励相关行为和兴奋性神经传递。新颖的概念框架是，VTA DA 和第 5/6 层 mPFC 锥体神经元中的 Girk 信号传导是一种早期的“成瘾障碍”，可通过接触可卡因来克服，为与渴望和复发相关的持久适应铺平道路。拟议的研究将结合切片电生理学和行为评估，这两种方法都利用一系列新型突变小鼠品系，并利用我们以前所未有的分子、解剖和时间精度扰乱 Girk 信号传导能力的最新进展。工作将集中在三个具体目标上：1) 了解可卡因对 VTA DA 神经元中 Girk 信号传导的急性抑制，2) 了解可卡因对 mPFC 锥体神经元中 Girk 信号传导的反复抑制，以及 3) 探究可卡因对 mPFC 锥体神经元中 Girk 信号传导的重复抑制。 VTA 和 mPFC 中的 Girk 信号传导与奖励相关行为的相关性。该项目的成功完成将对 Girk 信号传导与奖励相关行为的相关性产生新的见解，同时也强调此类信号传导在可卡因诱导的神经适应中的作用，而神经适应是成瘾关键方面（包括渴望和复发）的基础。因此，该项目针对国家药物滥用研究所的多个战略目标，包括预防和治疗目标，这些目标取决于扩大我们对基本神经生物学的理解，因为它与成瘾的神经回路有关。