Defining the Role for Orexin Transmission in Nicotine Reinforcement

定义食欲素传输在尼古丁强化中的作用

基本信息

批准号：
8240122
负责人：
Jonathan Alan Hollander
金额：
$ 14.85万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8240122
关键词：
Abstinence Accounting Animals Attention Automobile Driving Behavior Biological Brain Brain region Cancer Etiology Cause of Death Cells Cessation of life Chronic Complex Consumption Cues Data Detection Developed Countries Disease Dose Economics Effectiveness Goals Heart Diseases Human Hypothalamic structure Insula of Reil Intake Intravenous Investigation Knockout Mice Laboratories Lateral Lead Lentivirus Vector Lung diseases Malignant Neoplasms Mediating Motivation Mus National Institute of Drug Abuse Neurobiology Neurons Neuropeptides Nicotine Nicotine Dependence Pharmaceutical Preparations Pharmacotherapy Play Predisposition Process Property Psychological reinforcement Rattus Relapse Research Resistance Rewards Rodent Role SB-334867 Self Administration Self-Administered Signal Transduction Smoker Smoking Stimulus Stroke System Testing Time Tobacco Tobacco Dependence Tobacco use Training United States Viral Virus Wit addiction base cigarette smoking cost craving drug abstinence drug of abuse drug reward experience hypocretin insight motivated behavior novel novel therapeutics orexin 1 receptor orexin A orexin B orexin B receptor paired stimuli prevent psychobiologic receptor relating to nervous system research study reward circuitry smoking cessation social transmission process viral rescue

项目摘要

DESCRIPTION (provided by applicant): Discovered in the 1990s, orexin (or hypocretin)-containing neurons in the lateral hypothalamus are now receiving considerable attention for their possible role in regulating motivated behavior for drugs of abuse. Indeed, previous studies from our laboratory and others have shown that the orexin-1 receptor antagonist, SB- 334867 (given systemically or directly infused into the insular cortex) decreases intravenous nicotine self- administration in rats. However, the role of orexin-2 (OX2) signaling in mediating nicotine reinforcement is poorly understood. Further, little is known about the effects of abstinence on orexin signaling following repeated nicotine consumption and its precise role in driving relapse. These are critical issues since human smokers often feel 'cravings' and subsequently relapse following intermittent periods of abstinence. Here, the first aim of this proposal is to assess intravenous nicotine self-administration in mice lacking OX1 receptors (OX1-/-), test whether viral-mediated re-expression of OX1 receptors in the insular cortex of OX1-/- mice "rescues" deficits in nicotine intake, and investigate the role for OX2 receptors in nicotine reinforcement using novel pharmacological agents and OX1-/- mice. Given the susceptibility of addicts to relapse to smoking after periods of cessation, the goal of Aim 2 will be to determine the effectiveness of selective OX1 and OX2 receptor antagonists on nicotine seeking and taking behavior following different periods of drug abstinence (0, 7 or 30 days) in well trained rats. Wit drug-associated cues often elicitors of relapse for smokers, Aim 3 will investigate the effects of nicotine abstinence on the associative properties of orexin cell firing in the lateral hypothalamus This aim will entail electrophysiological recordings in behaving animals to determine if the activity of putative orexin neurons is altered following nicotine-paired cue presentation after extended periods of abstinence. Collectively, these experiments will provide important insight into the psychobiological mechanisms underlying nicotine addiction, and promise to yield a novel therapeutic strategy for treating human smokers. PUBLIC HEALTH RELEVANCE: As the major single cause of cancer-related deaths in the United States, nicotine addiction has devastating personal, economic and social cost. The PI will study the motivational and neural underpinnings of nicotine addiction by investigating the role of orexin signaling in rats and mice. Such investigations could lead to new pharmacotherapies aimed at preventing relapse in smokers who wish to remain drug free.

描述（由申请人提供）：在1990年代发现，横向下丘脑中含有神经元的Orexin（或低载素），现在因其在调节滥用药物的动机行为中的可能作用而受到极大关注。实际上，我们实验室和其他人的先前研究表明，Orexin-1受体拮抗剂SB-334867（全身或直接注入岛状皮质）降低了大鼠静脉注射尼古丁的自我给药。然而，对尼古丁增强培养基在介导尼古丁增强中的作用知之甚少。此外，对于反复消耗尼古丁及其在驱动复发中的精确作用后，禁欲对奥甲蛋白信号传导的影响知之甚少。这些是关键问题，因为人类吸烟者经常感到“渴望”，随后在间歇性禁欲期间复发。在这里，该提案的第一个目的是评估缺乏OX1受体（OX1 - / - ）的小鼠中静脉注射尼古丁自我给药，测试病毒介导的OX1 - / - 小鼠岛状皮质中OX1受体的重新表达营救“尼古丁摄入的缺陷，并使用新型药理剂和OX1 - / - 小鼠研究OX2受体在尼古丁增强中的作用。鉴于成瘾者在停止后对吸烟的复发的敏感性，目标2的目标是确定选择性的OX1和OX2受体拮抗剂对烟碱寻求烟碱的有效性几天）训练有素的老鼠。 WIT药物相关的提示通常会引起吸烟者的复发，AIM 3将调查戒酒对尼古丁的戒烟对下丘脑外侧下丘脑中Orexin细胞发射的关联性能的影响。这种目标在行为动物中需要进行电生理记录，以确定假定动物是否确定假定的甲骨素活性。尼古丁培养的提示表现后，神经元在戒酒长期后会改变。总的来说，这些实验将为尼古丁成瘾的心理生物学机制提供重要的见解，并有望产生一种新的治疗策略来治疗人类吸烟者。公共卫生相关性：作为美国与癌症相关死亡的主要原因，尼古丁成瘾具有毁灭性的个人，经济和社会成本。 PI将通过研究大鼠和小鼠中Orexin信号的作用来研究尼古丁成瘾的动机和神经基础。这样的调查可能会导致新的药物治疗，旨在防止希望保持无毒的吸烟者的复发。