Nicotinic contributions to affective behavior

描述(申请人提供)：烟瘾是一种多方面的生物行为现象，由尼古丁的主要强化作用以及尼古丁缓解焦虑的能力支持。我们和其他人的工作表明，含有烟碱型乙酰胆碱受体(？2*nAChRs；*表示与其他亚单位组装)的？2激活促进了尼古丁的主要增强作用，但关于尼古丁如何促进吸烟者焦虑的了解较少。这项提议将检验这样一个假设，即尼古丁使？2*nAChRs亚群失活支持类焦虑行为。激活后，nAChRs变得不敏感，而亚激活剂量的尼古丁优先使nAChRs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焦虑的行为，而高剂量的尼古丁会促进焦虑产生。这些研究的一个主要目标是确定哪些亚单位与？2结合在一起调节类似焦虑的行为。？2*nAChRs可被？-芋螺毒素MII(？-CMII)敏感性所分解。？-CMII敏感的？6？3？2*nAChRs选择性地表达于儿茶酚胺能核，在调节奖赏样行为的脑区终末优先表达。？-CMII不敏感？4？2*nAChRs在调节焦虑样行为的区域更普遍地表达，包括杏仁核和外侧隔。我们将使用转基因小鼠的？4和？6 nAChRs功能丧失或获得来测试？4？2*nAChRs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调节细胞内信号通路的外侧间隔变化，如细胞外调节激酶(ERK)，这与应激调节有关。利用对外侧隔区ERK信号的神经化学和分子操作，这些研究将在ERK信号的变化和焦虑样行为的表达之间建立功能联系。结合我们的基因技术，这些研究将确定2nAChR调节ERK是否是调节焦虑或焦虑产生的关键机制。这些拟议的研究将大大增加我们对尼古丁亚基与？2联合调节焦虑行为的理解，并确定这些nAChRs是否在外侧隔区发挥作用。总而言之，这项拟议的工作将提供关于这些受体的激活或抑制是否代表开发促进戒烟和缓解焦虑的新疗法的潜在策略的见解。

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.