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）：尽管许多吸烟者表示想要戒烟，但很少有人能够通过传统药物疗法做到这一点。今年 5 月，辉瑞公司获得 FDA 批准销售其戒烟药物伐尼克兰（伐尼克兰），伐尼克兰是一种烟酸的部分激动剂。所谓的选择性2 含有烟碱乙酰胆碱受体 (¿2*nAChRs) 数据积累表明 ¿2*nAChRs。 2*nAChR 对于尼古丁相关的多巴胺 (DA) 释放和尼古丁的主要增强作用是必需的。 2*nAChR 最近被认为具有调节条件强化 (CR) 的作用；也就是说，与主要强化物（如尼古丁）配对的线索对吸烟等行为的控制是主要目标。建议的实验是确定 ¿ 的子类是否2*nAChRs，由a-芋螺毒素MII敏感性分解，差异性地调节尼古丁的主要奖励作用与尼古丁增强CR的能力，就像a-芋螺毒素MII (a-CMII)不敏感的a4¿2*nAChRs，a-CMII敏感的， a6¿2¿3*nAChRs，也调节尼古丁刺激的 DA 释放，主要表达于。儿茶酚胺能神经元和纹状体 DA 末端高度富集，a6¿2¿3*nAChR 在尼古丁强化中的作用尚不清楚，尽管 a4 亚基对其对尼古丁奖励的贡献密切相关，但迄今为止还没有研究具体质疑是否存在这种作用。这些研究的具体目标 1 是确定与 ¿ 结合的 nAChR 亚基。 2 对于通过无偏尼古丁条件位置偏好 (CPP) 测量的尼古丁奖励效果是必要的，实验 1 将测试 ¿ 3 和 a4 nAChR 亚基敲除小鼠的尼古丁 CPP 水平发生改变 研究表明，腹侧被盖区 (VTA) 输注二氢-β-赤霉素 (DH¿E)（一种 ¿E 的选择性拮抗剂）。 2*nAChRs，阻断a-CMII的尼古丁内输注将确定VTA水平的MII敏感受体是否是尼古丁CPP所必需的，这些实验的具体目标2将确定a-CMII是否敏感和不敏感。的子类 ¿ 2*nAChR 差异性地调节基线 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 3 和 a4 基因敲除小鼠将接受巴甫洛夫判别方法训练，然后获得对伏隔核 (NAc) 核心的条件强化物的新反应，这对于基线 CR 的调节至关重要。调节尼古丁介导的 CR 促进的系统尚不清楚，伏隔核壳 DA 对于精神兴奋剂增强 CR 至关重要。目标 2 的第二个实验将使用。壳内输注 a-芋螺毒素 MII 和 DH¿ E 测试是否不同 ¿伏隔核水平的 2*nAChR 调节尼古丁刺激的 CR 升高。这些实验将开始确定支持尼古丁相关的 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。含有烟碱乙酰胆碱受体 (¿2*nAChR) 的 2 亚基对尼古丁具有最高的亲和力，并且在大脑中表达最广泛。辉瑞公司最近获得 FDA 和欧盟委员会的批准，上市其戒烟药物伐尼克兰（一种可减少吸烟量的化合物）。尽管伐尼克兰的长期成功率是之前批准的疗法的两倍，但针对支持特定行为的疗法。尼古丁依赖应该 1) 减少副作用，2) 改善更多吸烟者的戒烟结果。 2*nAChR 可以被α-芋螺毒素敏感性分解，这涉及尼古丁奖励效应的调节与尼古丁增强线索对行为的控制的能力，拟议的实验将为尼古丁戒烟治疗确定新的、更具选择性的目标。