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：
8413210
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 2013-12-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8413210
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.

描述（由申请人提供）：在 20 世纪 90 年代发现，外侧下丘脑中含有食欲素（或下丘脑分泌素）的神经元现在因其在调节滥用药物的动机行为中可能发挥的作用而受到相当多的关注。事实上，我们实验室和其他实验室之前的研究表明，食欲素 1 受体拮抗剂 SB-334867（全身给药或直接注入岛叶皮质）可减少大鼠静脉内尼古丁的自我给药。然而，人们对食欲素 2 (OX2) 信号在介导尼古丁强化中的作用知之甚少。此外，人们对反复摄入尼古丁后戒烟对食欲素信号传导的影响及其在驱动复发中的确切作用知之甚少。这些都是至关重要的问题，因为人类吸烟者经常感到“渴望”，并随后在间歇性戒烟后复发。在此，该提案的首要目的是评估缺乏OX1受体（OX1-/-）的小鼠静脉注射尼古丁自我给药，测试病毒介导的OX1受体在OX1-/-小鼠岛叶皮质中的重新表达是否存在“拯救”尼古丁摄入不足，并使用新型药物和 OX1-/- 小鼠研究 OX2 受体在尼古丁强化中的作用。鉴于成瘾者在戒烟一段时间后容易复吸，目标 2 的目标是确定选择性 OX1 和 OX2 受体拮抗剂对不同戒毒期（0、7 或 30）后尼古丁寻求和吸食行为的有效性。天）在训练有素的老鼠身上。与药物相关的线索通常会诱发吸烟者复吸，目标 3 将研究尼古丁戒断对下丘脑外侧食欲素细胞放电的关联特性的影响。该目标将需要对行为动物进行电生理记录，以确定假定的食欲素活性是否长时间戒烟后，神经元在尼古丁配对提示呈现后发生改变。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，并有望为治疗人类吸烟者提供一种新的治疗策略。