nAChR subunit contributions to nicotine dependent behaviors

nAChR 亚基对尼古丁依赖行为的贡献

• 批准号: 7489390
• 负责人: DARLENE H BRUNZELL
• 金额: $ 7.3万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489390
• 关键词: Adverse effects; Affinity; Agonist; Animals; Behavior; Binding; Brain; Chronic; Condition; Conotoxin; Corpus striatum structure; Cues; Data; Dihydro-beta-Erythroidine; Dopamine; Drosophila acetylcholine receptor alpha-subunit; Elevation; European; Genetic; Goals; Impairment; Infusion procedures; Knock-out; Knockout Mice; Lead; Marketing; Measures; Mediating; Medical; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nucleus Accumbens; Outcome; Performance; Pharmaceutical Preparations; Psychological reinforcement; Recording of previous events; Regulation; Reporting; Rewards; Role; Self Administration; Smoker; Smoking; Support System; System; Testing; Training; United States Food and Drug Administration; Up-Regulation; Ventral Tegmental Area; dopamine system; improved; knock-down; novel; preference; psychostimulant; receptor; reinforcer; research study; response; smoking cessation; success; varenicline

DESCRIPTION (provided by applicant): Though many smokers report wanting to quit, very few are able to do so with traditional medical therapies. In May of this year, Pfizer received FDA approval to market its smoking cessation drug, varenicline, a partial agonist with purported selectivity for the ¿2 containing nicotinic acetylcholine receptors (¿2*nAChRs). An accumulation of data indicates that the ¿2*nAChRs are necessary for nicotine associated dopamine (DA) release and for the primary reinforcing effects of nicotine. The ¿2*nAChRs have more recently been implicated for their role in regulating conditioned reinforcement (CR); that is to say, the control that cues paired with a primary reinforcer, such as nicotine, have over behaviors, such as smoking. The primary goal of the proposed experiments is to determine whether subclasses of ¿2*nAChRs, broken down by a-conotoxin MII sensitivity, differentially regulate nicotine's primary rewarding effects versus nicotine's ability to enhance CR. Like the a-conotoxin MII (a-CMII) insensitive a4¿2*nAChRs, the a-CMII sensitive, a6¿2¿3*nAChRs, also modulate nicotine-stimulated DA release. Chiefly expressed in catecholaminergic neurons and highly enriched at striatal DA terminals, the role of a6¿2¿3*nAChRs in nicotine reinforcement is not known. Although the a4 subunit is highly implicated for its contributions to nicotine reward, no studies to date have specifically questioned whether the a4 subunits are required for nicotine reward. Specific Aim 1 of these studies is to identify which nAChR subunits in combination with ¿2 are necessary for the rewarding effects of nicotine as measured by non-biased nicotine conditioned place preference (CPP). Experiment 1 will test ¿3 and a4 nAChR subunit knockout mice for altered levels of nicotine CPP. Studies have shown that ventral tegmental area (VTA)-infusion of dihydro-beta-erythroidine (DH¿E), a selective antagonist of the ¿2*nAChRs, blocks nicotine self administration. Intra-VTA infusion of a-CMII will determine whether MII sensitive receptors at the level of the VTA are required for nicotine CPP. Specific Aim 2 of these experiments will determine whether a-CMII sensitive and insensitive subclasses of ¿2*nAChRs differentially regulate baseline CR and the ability of prior chronic nicotine to enhance CR. ¿3 and a4 knockout mice with different histories of nicotine exposure will undergo Pavlovian discriminative approach training followed by acquisition of a new response with a conditioned reinforcer. DA projections to the nucleus accumbens (NAc) core are critical for regulation of CR at baseline. Although the systems that regulate nicotine-mediated facilitation of CR are unknown, nucleus accumbens shell DA is essential for psychostimulant enhancement of CR. The 2nd experiment of Aim 2 will use intra-shell infusion of a-conotoxin MII and DH¿E to test whether different ¿2*nAChRs at the level of the accumbens regulate nicotine stimulated elevations of CR. These experiments will begin to identify the systems that support nicotine associated enhancement of CR and in doing so will identify behaviorally relevant targets for nicotine cessation. Project De RRATIVE The ¿2 subunit containing nicotinic acetylcholine receptors (¿2*nAChR) have the highest affinity for nicotine and are the most widely expressed in the brain. Pfizer has recently received FDA and European Commission approval to market its smoking cessation drug, varenicline, a compound that reduces activity of these receptors that are important for nicotine dependence. Though varenicline's long-term success is double that of previously approved therapies, treatments that are targeted against specific behaviors that support nicotine dependence ought to 1) lead to fewer side effects and 2) improve outcomes for smoking cessation in a greater diversity of smokers. In determining that ¿2*nAChRs can be broken down by a-conotoxin sensitivity in regard to regulation of nicotine's rewarding effects versus nicotine's ability to enhance the control that cues have over behavior, the proposed experiments will identify novel, more selective targets for nicotine cessation therapy.

描述（由申请人提供）：虽然许多吸烟者报告想要戒烟，但很少有人能够通过传统的医学疗法戒烟。今年5月，辉瑞公司获得FDA批准销售其戒烟药物伐尼克兰，这是一种部分激动剂，据称对含有烟碱乙酰胆碱受体（nAChRs）的nAChRs具有选择性。数据的积累表明，<$2 * nAChR对于尼古丁相关的多巴胺（DA）释放和尼古丁的主要强化作用是必需的。该2* nAChR最近被认为在调节条件强化（CR）中起作用;也就是说，与主要刺激物（如尼古丁）配对的线索的控制具有过度行为，如吸烟。所提出的实验的主要目标是确定通过α-芋螺毒素MII敏感性分解的N2 * nAChR的亚类是否差异地调节尼古丁的主要奖励作用与尼古丁增强CR的能力。与α-芋螺毒素MII（a-CMII）不敏感的α 4 <$2 * nAChR一样，α-CMII敏感的α 6 <$2 <$3 * nAChR也调节尼古丁刺激的DA释放。chirons在儿茶酚胺能神经元中表达，并在纹状体DA终末高度富集，α 6 <$2 <$3 *nAChRs在尼古丁强化中的作用尚不清楚。虽然a4亚基与尼古丁奖赏密切相关，但迄今为止还没有研究明确质疑a4亚基是否是尼古丁奖赏所必需的。这些研究的具体目标1是确定哪些nAChR亚基与nAChR亚基2的组合对于尼古丁的奖赏效应是必要的，如通过无偏尼古丁条件性位置偏好（CPP）测量的。实验1将测试nAChR 3和a4亚基敲除小鼠尼古丁CPP水平的改变。研究表明，腹侧被盖区（VTA）输注二氢-β-赤藓定（DH <$E）（<$2 * nAChR的选择性拮抗剂）可阻断尼古丁自我给药。VTA内输注a-CMII将确定尼古丁CPP是否需要VTA水平的MII敏感受体。这些实验的具体目标2将确定a-CMII敏感和不敏感的nAChR亚类是否差异调节基线CR和先前慢性尼古丁增强CR的能力。具有不同尼古丁暴露史的α 3和α 4基因敲除小鼠将经历巴甫洛夫辨别方法训练，然后用条件反射器获得新的反应。DA投射到丘脑核（NAc）核心对于基线时CR的调节至关重要。虽然调节尼古丁介导的促进CR的系统是未知的，但延髓核壳DA对CR的精神兴奋剂增强是必不可少的。目标2的第二个实验将使用α-芋螺毒素MII和DH E的壳内输注来测试在烟碱水平上的不同的nAChR是否调节烟碱刺激的CR升高。这些实验将开始以确定支持尼古丁相关CR增强的系统，并在此过程中确定尼古丁戒烟的行为相关目标。Project De RRATIVE含有烟碱乙酰胆碱受体（nAChR）的2亚基对尼古丁的亲和力最高，并且在大脑中表达最广泛。辉瑞公司最近获得了FDA和欧盟委员会的批准，可以销售其戒烟药物伐尼克兰，这是一种化合物，可以降低这些对尼古丁依赖很重要的受体的活性。虽然伐尼克兰的长期成功是以前批准的疗法的两倍，但针对支持尼古丁依赖的特定行为的治疗应该1）导致更少的副作用，2）改善更多样化吸烟者的戒烟结果。在确定…2* nAChR可以被α-芋螺毒素敏感性分解，关于尼古丁的奖励效应的调节与尼古丁增强线索对行为的控制的能力，所提出的实验将鉴定用于尼古丁戒断治疗的新的、更具选择性的靶标。