DISSECTING DYNORPHIN-KAPPA OPIOID MEDIATED REINSTATEMENT OF NICOTINE PREFERENCE

剖析强啡肽-卡帕阿片类药物介导的尼古丁偏好恢复

• 批准号: 9277608
• 负责人: Michael R. Bruchas
• 金额: $ 3.66万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277608
• 关键词: Agonist; Amygdaloid structure; Animals; Anxiety; Behavior; Biological; Biological Assay; Biological Neural Networks; Brain; Cells; Cessation of life; Chemosensitization; Cocaine; Coupled; Cre-LoxP; Dependovirus; Drug abuse; Dynorphins; Genetic; Health; Human; Internal Ribosome Entry Site; Knock-out; Knockout Mice; Knowledge; Learning; Link; LoxP-flanked allele; MAP Kinase Gene; MAPK14 gene; Measures; Mediating; Memory; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mood Disorders; Morphine; Mus; Neurons; Neuropharmacology; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nucleus Accumbens; Open Reading Frames; Opioid; Opioid Receptor; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Prevention; Process; Receptor Activation; Regulation; Relapse; Reporting; Research Project Grants; Rewards; Risk; Rodent; Role; Self Administration; Serotonergic System; Signal Pathway; Signal Transduction; Site; Stress; Structure of terminal stria nuclei of preoptic region; System; Techniques; Testing; Time; Tissues; Tobacco; Viral; alcohol seeking behavior; cell type; dorsal raphe nucleus; drug of abuse; drug seeking behavior; dysphoria; gain of function; in vivo; insight; interdisciplinary approach; kappa(1) opioid receptor; mouse model; mutant; neural circuit; novel; novel therapeutic intervention; novel therapeutics; optogenetics; preference; promoter; recombinase; relating to nervous system; viral rescue

DESCRIPTION (provided by applicant): Activation of kappa opioid receptors (KOR) in humans elicits dysphoria, and KOR activation by agonists or by stress-induced dynorphin release in rodents produces reinstatement of drug seeking. The dysphoric/aversive effects of dynorphin/KOR system activity have been linked to increased cocaine self-administration, and cause reinstatement of cocaine seeking behaviors. While many reports of KOR dependent regulation of cocaine, morphine, and alcohol seeking exist, there are very few studies examining the role and mechanisms of stress-induced dynorphin-KOR activity on nicotine reinstatement. Despite recent efforts, nicotine use is at an all time high, is responsible for millions of deaths each year and remains one of the most difficult drugs to quit. The neural networks and cellular-molecular mechanisms responsible for KOR-dependent nicotine reinstatement are not understood. Given nicotine's diverse pharmacological profile and interaction within multiple circuits, understanding how dynorphin neural circuits and KOR activation causes nicotine reinstatement will provide novel, valuable, and important insights and suggest new therapeutic approaches to the treatment and prevention of stress-related nicotine relapse. While evidence shows a key role for KOR-dependent inhibition in ventral tegmental (VTA) nucleus Accumbens (NAc) circuits, recent evidence has strongly implicated dynorphin activation of p38 MAPK in the serotonergic dorsal raphe nucleus (DRN) as required for KOR-dependent reinstatement and aversion. The role of each pathway in nicotine reinstatement is not known, so we propose to methodically dissect how activation of KOR, either by stress-induced dynorphin, optogenetic modulation of dynorphin/CRF release, or systemic administration of a selective KOR agonist, results in reinstatement of nicotine conditioned place preference. To accomplish this we propose the following Aims using an array of multidisciplinary approaches: 1) to determine the role of dynorphin/KOR activity in serotonergic circuits as necessary and sufficient for stress-induced nicotine preference using viral rescue ("gain of function"), in vivo pharmacology, and mouse genetics to assess KOR in circuits mediating stress-induced and dynorphin/KOR-mediated reinstatement of nicotine preference. 2) to measure the effects of p38 MAPK activation in circuits required for stress-induced reinstatement of nicotine preference. 3) To use a novel mouse line coupled with optogenetic approaches to dissect dynorphinergic neural inputs into key sites of KOR action mediating reinstatement of nicotine preference. The proposed studies would test our central hypothesis that stress and KOR-induced reinstatement of nicotine reward is mediated as consequence of dynorphin-KOR-dependent activation of downstream signaling pathways in selected neural circuits.

描述（由申请方提供）：人类κ阿片受体（KOR）的激活会引发烦躁不安，而啮齿动物中激动剂或应激诱导的强啡肽释放激活KOR会导致药物寻求的恢复。强啡肽/KOR系统活性的焦虑/厌恶效应与可卡因自我给药增加有关，并导致可卡因寻求行为的恢复。虽然存在许多关于可卡因、吗啡和酒精寻求的KOR依赖性调节的报道，但很少有研究探讨应激诱导的强啡肽-KOR活性对尼古丁恢复的作用和机制。尽管最近做出了努力，但尼古丁的使用仍处于历史最高水平，每年造成数百万人死亡，仍然是最难戒烟的药物之一。负责KOR依赖性尼古丁恢复的神经网络和细胞分子机制尚不清楚。鉴于尼古丁的多种药理学特征和多个回路内的相互作用，了解强啡肽神经回路和KOR激活如何导致尼古丁复吸将提供新颖、有价值和重要的见解，并提出治疗和预防应激相关尼古丁复吸的新治疗方法。虽然有证据表明，在腹侧被盖（VTA）的伏隔核（NAc）电路的关键作用，KOR依赖性抑制，最近的证据强烈暗示强啡肽激活的p38 MAPK的中缝背核（DRN）所需的KOR依赖性恢复和厌恶。每个途径在尼古丁恢复中的作用尚不清楚，因此我们建议系统地剖析如何激活KOR，无论是通过应激诱导的强啡肽，强啡肽/CRF释放的光遗传学调节，还是全身给予选择性KOR激动剂，导致尼古丁条件性位置偏好的恢复。为了实现这一点，我们提出了以下目标，使用一系列多学科的方法：1）确定强啡肽/KOR活性在尼古丁能回路中的作用，作为必要的和足够的压力诱导的尼古丁偏好使用病毒救援（“获得功能”），体内药理学和小鼠遗传学，以评估KOR在回路介导的压力诱导和强啡肽/KOR介导的尼古丁偏好的恢复。2)测量压力诱导的尼古丁偏好恢复所需回路中p38 MAPK激活的作用。3)使用一种新的小鼠系结合光遗传学方法，将强啡肽能神经输入解剖到介导尼古丁偏好恢复的KOR作用的关键位点。拟议的研究将测试我们的中心假设，即压力和KOR诱导的尼古丁奖励的恢复是介导的强啡肽-KOR依赖性激活的下游信号通路在选定的神经回路的结果。