Nicotinic contributions to affective behavior

烟碱对情感行为的贡献

• 批准号: 8505471
• 负责人: DARLENE H BRUNZELL
• 金额: $ 31.76万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505471
• 关键词: Affect; Affective; Amygdaloid structure; Animals; Anti-Anxiety Agents; Anxiety; Area; Behavior; Behavioral Assay; Biological Assay; Boxing; Brain; Cell Nucleus; Cognition; Conotoxin; Cyclophosphamide; Data; Development; Dominant-Negative Mutation; Dose; Drosophila acetylcholine receptor alpha-subunit; Emotional; Extracellular Signal Regulated Kinases; Genetic; Goals; Grant; Infusion procedures; Injection of therapeutic agent; Lateral; Lead; Light; Link; MEKs; Measures; Mediating; Molecular; Mus; Mutant Strains Mice; Neuromodulator; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotinic Receptors; Pattern; Phenotype; Phosphorylation; Phosphotransferases; Point Mutation; Proteins; Receptor Inhibition; Regulation; Rewards; Second Messenger Systems; Signal Pathway; Signal Transduction; Smoker; Stimulus; Stress; Testing; Tobacco Dependence; Transfection; Transgenic Mice; U-0126; Viral; Viral Vector; Wild Type Mouse; Work; attenuation; behavior observation; biobehavior; desensitization; erythroidine; extracellular; gain of function; genetic technology; inhibitor/antagonist; insight; neurochemistry; novel; null mutation; receptor; receptor function; research study; response; selective expression; smoking cessation; tissue culture

DESCRIPTION (provided by applicant): Tobacco addiction is a multifaceted biobehavioral phenomenon that is supported by the primary reinforcing effects of nicotine as well as by nicotine's ability to relieve anxiety. Our work and others have shown that activation of ?2 containing nicotinic acetylcholine receptors (?2*nAChRs; *denotes assembly with other subunits) promotes the primary reinforcing effects of nicotine, but less is known regarding how nicotine promotes anxiolysis in smokers. This proposal will test the hypothesis that inactivation of subsets of ?2*nAChRs by nicotine supports anxiolytic-like behavior. After activation, nAChRs become desensitized, and subactivating doses of nicotine preferentially desensitize nAChRs. This hypothesis is further supported by studies showing that low doses of nicotine lead to anxiolytic-like behavior whereas high doses promote anxiogenisis. A primary goal of these studies is to identify which subunits in combination with ?2 regulate anxiety-like behavior. ?2*nAChRs can be broken down by ?-conotoxin MII (?-CMII) sensitivity. The ?-CMII- sensitive ?6?3?2*nAChRs are selectively expressed in catecholaminergic nuclei with preferential expression on terminals in brain areas that regulate reward-like behavior. The ?-CMII insensitive ?4?2*nAChRs are more ubiquitously expressed in regions that also regulate anxiety-like behavior, including the amygdala and the lateral septum. We will use mice genetically altered to have a loss or gain of function of their ?4 and ?6 nAChRs to test if ?4?2*nAChRs preferentially regulate affective behaviors. These studies will further determine if nicotine acts through ?4?2*nAChRs or ?6?3?2*nAChRs to regulate lateral septal changes in intracellular signaling pathways, such as extracellular regulated kinase (ERK), that are implicated in regulation of stress. Using neurochemical and molecular manipulation of ERK signaling in the lateral septum, these studies will make a functional link between changes in ERK signaling and expression of anxiety-like behavior. Overlaid with our genetic technologies, these studies will identify if ?2*nAChR regulation of ERK is a critical mechanism by which ?2*nAChRs regulate anxiolysis or anxiogenisis. The proposed studies will substantially increase our understanding of which nicotinic subunits in combination with ?2 regulate anxiety behavior and determine whether these nAChRs exert their effects in the lateral septum. Collectively, this proposed work will provide insights into whether activation or inhibition of these receptors represents potential strategies for development of novel therapies to promote smoking cessation and to relieve anxiety.

描述（由申请人提供）：烟草成瘾是一种多方面的生物行为现象，尼古丁的主要强化作用以及尼古丁缓解焦虑的能力都支持这一现象。我们和其他人的工作表明，含有烟碱乙酰胆碱受体（?2*nAChR；*表示与其他亚基组装）的α2的激活可促进尼古丁的主要增强作用，但关于尼古丁如何促进吸烟者的抗焦虑作用，人们知之甚少。该提案将检验尼古丁使 2*nAChR 子集失活支持抗焦虑样行为的假设。激活后，nAChR 变得脱敏，亚激活剂量的尼古丁优先使 nAChR 脱敏。研究进一步支持了这一假设，研究表明低剂量的尼古丁会导致类似抗焦虑的行为，而高剂量的尼古丁会促进抗焦虑作用。这些研究的主要目标是确定哪些亚基与 β2 结合调节焦虑样行为。 ?2*nAChRs 可以被 ?-芋螺毒素 MII (?-CMII) 敏感性分解。 α-CMII敏感的α6α3α2*nAChR选择性地在儿茶酚胺能核中表达，并优先在调节奖赏样行为的大脑区域的末端上表达。 α-CMII 不敏感的 α4?2*nAChR 在也调节焦虑样行为的区域中更普遍表达，包括杏仁核和外侧隔膜。我们将使用经过基因改造使其 α4 和 β6 nAChR 功能丧失或获得的小鼠来测试 β4？2*nAChR 是否优先调节情感行为。这些研究将进一步确定尼古丁是否通过 ?4?2*nAChRs 或 ?6?3?2*nAChRs 来调节细胞内信号通路中的侧隔膜变化，例如与压力调节有关的细胞外调节激酶 (ERK) 。这些研究利用神经化学和分子操作对外侧隔膜中的 ERK 信号传导进行操作，将在 ERK 信号传导的变化与焦虑样行为的表达之间建立功能联系。与我们的基因技术相结合，这些研究将确定 2*nAChR 对 ERK 的调节是否是 2*nAChR 调节抗焦虑或抗焦虑的关键机制。拟议的研究将大大增加我们对哪些烟碱亚基与 β2 结合调节焦虑行为的理解，并确定这些 nAChR 是否在侧隔膜中发挥作用。总的来说，这项拟议的工作将深入了解这些受体的激活或抑制是否代表开发新疗法以促进戒烟和缓解焦虑的潜在策略。