Nicotinic contributions to affective behavior

烟碱对情感行为的贡献

基本信息

批准号：
8194808
负责人：
DARLENE H BRUNZELL
金额：
$ 33.1万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
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/8194808
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Nicotinic receptors function largely as neuromodulators in the brain with consequent effects of their activation or inhibition on cognition, reward and affective behavior. Although most neurotransmitters exert their effects via second messenger systems, few studies have made functional links between nicotine-associated changes in intracellular signaling and behaviors that are relevant to nicotine and tobacco addiction. The proposed studies will identify selective nicotinic subunit regulation of signaling pathways that support affective behaviors.

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，它得到了尼古丁的主要增强作用以及尼古丁缓解焦虑的能力的支持。我们的工作和其他工作表明，含有烟碱乙酰胆碱受体的激活（？2 *nachrs; *表示与其他亚基的组装）促进了尼古丁的主要增强作用，但是关于尼古丁如何促进吸烟者中的抗焦虑症的较少已知。该提议将检验以下假设：尼古丁对nachrs的子集的灭活支持抗焦虑样行为。激活后，NACHR脱敏，尼古丁的亚激活剂量优先使NACHR脱敏。这一假设得到的研究进一步支持，表明低剂量的尼古丁会导致类似抗焦虑的行为，而高剂量促进了焦虑症。这些研究的主要目标是确定哪些亚基与？2调节焦虑样行为。？2*NACHR可以通过？-ototoxin mii（？cmii）敏感性分解。？-cmii-sentiment？6？3？2*NACHR在Catecholamin能核中有选择地表达，在调节奖励样行为的大脑区域中具有优先表达。？-CMII不敏感的？4？2*NACHRS在还调节焦虑症行为（包括杏仁核和外侧隔膜）的区域中更加普遍表达。我们将使用遗传改变的小鼠具有其？4和6 nAChR的功能损失或增益，以测试？4？2*NACHR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调节细胞内信号传导途径的侧隔变化，例如细胞外调节激酶（ERK），与应力调节有关。使用侧隔中ERK信号传导的神经化学和分子操纵，这些研究将在ERK信号传导的变化与焦虑样行为表达之间建立功能联系。这些研究与我们的遗传技术覆盖了，这些研究将确定eRK的NACHR调节是否是一种关键机制？拟议的研究将大大提高我们对哪些烟碱亚基结合使用？2调节焦虑行为的理解，并确定这些NACHR是否在外侧隔膜中发挥作用。总的来说，这项拟议的工作将提供有关激活或抑制这些受体的见解，代表了开发新疗法以促进戒烟和缓解焦虑的潜在策略。公共卫生相关性：烟碱受体在很大程度上充当了大脑中的神经调节剂，因此其激活或抑制对认知，奖励和情感行为的影响。尽管大多数神经递质通过第二信使系统发挥其影响，但很少有研究在尼古丁相关的细胞内信号传导变化与与尼古丁和烟草成瘾有关的行为之间建立了功能联系。拟议的研究将确定支持情感行为的信号通路的选择性烟碱亚基调节。