Relevance and plasticity of inhibitory metabotropic signaling in reward circuits

描述（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，即使在长期戒断后也是如此。仅在美国，与吸毒成瘾相关的成本，包括生产力损失，健康问题和犯罪，估计每年就有6000亿美元。我们对药物奖赏、渴望和复发的神经化学、分子和细胞机制的了解有限，阻碍了我们有效应对这一重大公共卫生问题的能力。这项建议的前提是，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。该提案的重点是一种形式的抑制信号及其相关性的细胞和行为的影响，急性和反复接触可卡因。我们在过去十年的工作已经揭示了许多滥用药物（包括可卡因）的行为效应依赖于G蛋白门控内向整流K+（Girk/KIR 3）通道。最近，我们已经发现，在体内可卡因暴露抑制Girk信号的多巴胺（DA）神经元的腹侧被盖区（VTA）和内侧前额叶皮层（第5/6层mPFC锥体神经元）的多巴胺能输出神经元，神经元群体有助于奖励相关的行为效应的急性和重复可卡因暴露。本项目的目标是了解可卡因如何抑制腹侧被盖区DA和第5/6层mPFC锥体神经元中的Girk信号，以及这些适应如何影响中皮质边缘奖赏回路中的奖赏相关行为和兴奋性神经传递。新的概念框架是，腹侧被盖区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”，可卡因暴露可以克服这种障碍，为与渴望和复发相关的持久适应铺平了道路。拟议的研究将结合联合收割机切片电生理和行为评估，这两种方法都利用了一种新的突变小鼠品系阵列，并利用了我们以前所未有的分子、解剖和时间精度干扰Girk信号传导能力的最新进展。本研究将集中于三个具体目标：1）了解可卡因诱导的VTA DA神经元中Girk信号的急性抑制，2）了解可卡因诱导的mPFC锥体神经元中Girk信号的重复抑制，以及3）探索VTA和mPFC中Girk信号与奖励相关行为的相关性。这个项目的成功完成将产生新的见解Girk信号与奖励相关行为的相关性，同时也突出了这种信号在可卡因诱导的神经适应中的作用，这些神经适应是成瘾的关键方面，包括渴望和复发。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，这取决于扩大我们对基本神经生物学的理解，因为它涉及成瘾的潜在回路。

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.