Nicotinic contributions to affective behavior

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，它由尼古丁的初级强化作用和尼古丁的缓解焦虑的能力支持。我们和其他人的研究表明？2含有尼古丁乙酰胆碱受体（?2* nachr； *表示与其他亚基组装）促进尼古丁的初级强化作用，但关于尼古丁如何促进吸烟者的焦虑缓解尚不清楚。这一提议将验证一个假设，即？尼古丁的2* nachr支持焦虑样行为。激活后，nAChRs变得脱敏，亚激活剂量的尼古丁优先使nAChRs脱敏。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，这进一步支持了这一假设。这些研究的主要目标是确定哪些亚基与？2 .调节类焦虑行为。？2* nachr可以通过？-贝壳毒素MII (？-CMII)的敏感性。的吗?- cmii敏感？6?3？2* nachr选择性表达于儿茶酚胺能核中，优先表达于调节奖赏样行为的脑区终末。的吗?-CMII不敏感？2* nachr在调节焦虑样行为的区域更普遍地表达，包括杏仁核和侧隔。我们将使用经过基因改造的老鼠，让它们失去或获得它们的功能。4和？6个nachr来测试？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？2* nachr还是6 * nachr ？2*nAChRs调节外侧间隔细胞内信号通路的变化，如细胞外调节激酶（ERK），这与应激调节有关。通过对侧隔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。与我们的基因技术相结合，这些研究将确定是否？2*nAChR调控ERK的关键机制是？2* nachr调节焦虑缓解或焦虑反应。拟议的研究将大大增加我们对哪些尼古丁亚基与？2调节焦虑行为，并确定这些nachr是否在外侧隔膜中发挥作用。总的来说，这项拟议的工作将为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提供见解。

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.