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，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种现象。我们的工作和其他人已经表明，激活？2含有烟碱乙酰胆碱受体（？2*nAChRs;* 表示与其他亚基的组装）促进尼古丁的主要强化作用，但关于尼古丁如何促进吸烟者的抗焦虑作用知之甚少。这项建议将测试的假设，失活的子集？尼古丁的2* nAChR支持抗焦虑样行为。激活后，nAChR变得脱敏，亚激活剂量的尼古丁优先脱敏nAChR。这一假设得到了研究的进一步支持，研究表明低剂量的尼古丁会导致抗焦虑样行为，而高剂量则会促进焦虑。这些研究的一个主要目标是确定哪些亚基与？2.调节焦虑样行为。? 2* nAChR可以通过以下方式分解：芋螺毒素MII（？CMII）灵敏度。什么？- CMII-敏感？六个？三个？2* nAChR选择性地表达在儿茶酚胺能核中，并优先表达在调节奖励样行为的大脑区域的末端。什么？- CMII不敏感？四个？2* nAChR在也调节焦虑样行为的区域中更普遍地表达，包括杏仁核和外侧隔。我们将使用基因改变的老鼠，使它们的功能丧失或获得？4、？6 nAChR测试如果？四个？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？四个？2* nAChR或？六个？三个？2* nAChR调节细胞内信号传导途径中的侧隔变化，如细胞外调节激酶（ERK），其涉及应激的调节。利用神经化学和分子操纵ERK信号在侧隔，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调节ERK是一个关键机制，通过什么？2* nAChR调节抗焦虑作用或抗焦虑作用。拟议的研究将大大增加我们的理解，哪些烟碱亚基结合？2调节焦虑行为，并确定这些nAChRs是否在外侧隔发挥作用。总的来说，这项拟议的工作将提供洞察这些受体的激活或抑制是否代表了开发新疗法以促进戒烟和缓解焦虑的潜在策略。

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.