Role of Orexin-1 Receptors in Nicotine Reinforcement

Orexin-1 受体在尼古丁强化中的作用

基本信息

批准号：
7579767
负责人：
Jonathan Alan Hollander
金额：
$ 5.01万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7579767
关键词：
A Mouse Accidents Acquired Immunodeficiency Syndrome Affinity Age Alcohols American Area Attenuated Behavior Brain Brain region Cessation of life Circadian Rhythms Cocaine Consumption Data Detection Development Disease Dose Drug usage Fire - disasters Genetic Habits Health Heroin Homicide Human Hypothalamic structure Intake Intravenous Investigation Knock-out Knockout Mice Laboratories Lateral Measures Metabolic Morphine Mus National Institute of Drug Abuse Neurobiology Neurons Neuropeptides Nicotine Nicotine Dependence Population Procedures Process Psychological reinforcement Rattus Reinforcement Schedule Reporting Research Rewards Role SB-334867 Self Administration Self Stimulation Sleep Smoker Stress Structure of terminal stria nuclei of preoptic region Substance abuse problem Suicide Surveys System Therapeutic Tobacco Tobacco use Training Ventral Tegmental Area addiction alcohol seeking behavior base drug abstinence drug reinforcement drug reward drug seeking behavior economic cost experience feeding hypocretin insight novel novel therapeutics orexin 1 receptor orexin A orexin B orexin B receptor psychobiologic receptor reward circuitry smoking cessation social treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Numerous investigations have shown that orexin-containing neurons that arise within the hypothalamus are critical regulators of sleep and feeding processes. In addition, very recent findings have implicated orexin systems in drug-seeking behaviors. For example, previous studies in our laboratory have shown that the orexin-1 receptor antagonist, SB-334867, blocked stress-induced reinstatement of extinguished cocaine responding in rats. Therefore, the blockade of orexin-1 receptors may be an effective strategy for the treatment of substance abuse disorders. However, the role of orexin-1 receptors in regulating the reinforcing effects of nicotine has not been assessed. Here, the first aim of this application will be to evaluate the effects of SB-334867 on the reinforcing effects of nicotine. To accomplish this task, the PI will utilize intravenous self-administration and intracranial self-stimulation procedures in well-trained rats to determine if SB-334867 decreases nicotine consumption and abolishes the stimulatory effects of nicotine on brain reward systems. The second aim of this proposal will be to identify neuroanatomical substrates of the brain reward system that regulate nicotine reinforcement via orexin-1 receptors. Specifically, the PI will microinfuse SB-334867 into the bed nucleus of the stria terminalis (BNST) or ventral tegmental area (VTA) to determine if blockade of orexin-1 receptors in these areas decreases nicotine intake in rats. While SB- 334867 certainly antagonizes the orexin-1 receptor, it is derived from a class of compounds that has high affinity for other non-orexin receptor classes as well. Indeed, it is presently unclear if SB-334867 acts only at orexin-1 receptors, or has 'off-target' effects at other receptor classes that may confound interpretation of data using this compound. Therefore, the third aim will directly assess the importance of the orexin-1 receptor in nicotine reinforcement by evaluating the acquisition of intravenous nicotine self-administration in orexin-1 receptor knockout mice compared with wildtype littermates. Collectively, these studies will provide important insights into psychobiological mechanisms of nicotine dependence processes, and promise to yield a novel therapeutic strategy for the treatment for human nicotine addiction. The devastating personal, social and economic cost of nicotine addiction has generated much research into understanding how the brain processes drug reward, and has motivated efforts to develop novel treatment strategies for treating the disorder. The experiments presented in this application investigate the role of orexin-1 receptors in nicotine reinforcement in rats and mice. Based on our preliminary research, blockade of orexin receptors may be a viable strategy to aid smokers who wish to quit their habit.

描述（由申请人提供）：许多调查表明，下丘脑内出现的含有Orexin的神经元是睡眠和喂养过程的关键调节剂。此外，最近的发现将Orexin Systems与寻求药物的行为有关。例如，我们实验室中的先前研究表明，Orexin-1受体拮抗剂SB-334867阻塞了应力诱导的大鼠可卡因响应的恢复。因此，封锁Orexin-1受体可能是治疗药物滥用障碍的有效策略。但是，尚未评估Orexin-1受体在调节尼古丁的增强作用中的作用。在这里，该应用程序的第一个目的是评估SB-334867对尼古丁增强作用的影响。为了完成这项任务，PI将利用训练有素的大鼠中静脉内自我管理和颅内自我刺激程序，以确定SB-334867是否会降低尼古丁的消耗并消除尼古丁对脑奖励系统的刺激作用。该提案的第二个目的是确定通过Orexin-1受体调节尼古丁增强的大脑奖励系统的神经解剖基底物。具体而言，PI将将SB-334867微源成质末端（BNST）或腹侧换段面积（VTA）的床核，以确定这些区域中Orexin-1受体的阻断是否会降低大鼠的尼古丁摄入量。虽然SB-334867肯定会拮抗Oxin-1受体，但它源自一类对其他非蛋白质受体类别具有高亲和力的化合物。实际上，目前尚不清楚SB-334867是仅在Orexin-1受体上起作用，还是在其他受体类别中具有“脱靶”效应，这些效应可能会使用该化合物混淆数据的解释。因此，第三个目标将直接评估Orexin-1受体在尼古丁增强中的重要性，通过评估与野生型同窝同伙相比，在Orexin-1受体敲除小鼠中获得静脉注射尼古丁自我给药。总的来说，这些研究将为尼古丁依赖过程的心理生物学机制提供重要的见解，并有望为人类尼古丁成瘾的治疗产生一种新颖的治疗策略。尼古丁成瘾的毁灭性个人，社会和经济成本已经为了解大脑如何处理药物奖励而产生了许多研究，并激发了制定新颖治疗策略来治疗该疾病的奖励。本应用中提出的实验研究了Orexin-1受体在大鼠和小鼠中尼古丁增强中的作用。根据我们的初步研究，封锁Orexin受体可能是帮助希望戒烟的吸烟者的可行策略。