Nicotine-Mediated behavioral Consequences of Nicotinic Receptor Upregulation

尼古丁介导的烟碱受体上调的行为后果

基本信息

批准号：
8829812
负责人：
ANDREW R TAPPER
金额：
$ 24.75万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8829812
关键词：
Accounting Acetylcholine Adult Affect Agonist Animals Automobile Driving Behavior Behavioral Binding Biological Assay Brain Brain region Cations Cells Cessation of life Chronic Complex Consensus Control Animal Dependence Dopamine Dose Drosophila acetylcholine receptor alpha-subunit Etiology Exposure to FOS gene Fluorescence Microscopy Frequencies Gene Delivery Genes Glutamate Decarboxylase Goals Health Individual Interneurons Ligands Link Measures Mediating Methods Midbrain structure Molecular Target Mus Neurons Neurotransmitters Nicotine Nicotine Dependence Nicotinic Receptors Nucleus Accumbens Pathway interactions Point Mutation Property Psychological reinforcement Rattus Rewards Role Slice Smoking Technology Testing Tobacco Tobacco smoke Up-Regulation Ventral Tegmental Area Viral base biophysical properties biophysical techniques desensitization drug of abuse environmental tobacco smoke exposure gain of function gene delivery system insight mortality novel preference receptor receptor upregulation response reward circuitry selective expression smoking cessation targeted treatment therapy design voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Chronic exposure to tobacco smoke accounts for ~5 million deaths per year making health complications from smoking the primary cause of preventable mortality in the world. Nicotine, the addictive component of tobacco, binds to and activates neuronal nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels that are normally activated by the endogenous neurotransmitter, acetylcholine. Nicotine initiates dependence by activating neurons within the ventral tegmental area (VTA) of the mesocorticolimbic reward circuitry, ultimately driving the release of dopamine (DA) within the nucleus accumbens, a phenomenon widely associated with the rewarding or reinforcing value of nicotine. A large variety of nAChR subunit genes are expressed in both VTA DAergic projection neurons and GABAergic interneurons but activation of nAChRs containing alpha4 and beta2 subunits in the VTA are most critical for the rewarding properties of nicotine. Exposure to chronic nicotine functionally upregulates nAChRs in various brain regions although the behavioral consequence of this upregulation is unknown. In the midbrain, nAChRs containing the alpha4 subunit are selectively upregulated in GABAergic neurons but not DAergic neurons. The goal of this R21 proposal is to gain insight into how this neuronal subtype selective functional upregulation of the alpha4 subunit affects nicotine reward behavior. Specific aim one will use viral-mediated gene delivery to selectively express gain-of-function alpha4 subunits in VTA GABAergic neurons of mice and measure nicotine-mediated reward behavior compared to control animals. Specific aim two will use immunohistochemical and biophysical approaches to determine how increased activation of GABAergic neurons by nicotine affects VTA DAergic neuron activity. The results from these studies will not only help define the role of GABAergic neurons in nicotine reward, but should also unmask behavioral consequences of nAChR upregulation.

描述（由申请人提供）：每年约 500 万人因长期接触烟草烟雾而死亡，这使得吸烟引起的健康并发症成为世界上可预防死亡的主要原因。尼古丁是烟草的成瘾成分，可结合并激活神经元烟碱乙酰胆碱受体 (nAChR)，这是一种配体门控阳离子通道，通常由内源性神经递质乙酰胆碱激活。尼古丁通过激活中皮质边缘奖赏回路腹侧被盖区 (VTA) 内的神经元来引发依赖性，最终驱动伏隔核内多巴胺 (DA) 的释放，这种现象与尼古丁的奖赏或强化价值广泛相关。多种 nAChR 亚基基因在 VTA DA 能投射神经元和 GABA 能中间神经元中表达，但 VTA 中含有 α4 和 β2 亚基的 nAChR 的激活对于尼古丁的奖励特性最为关键。长期接触尼古丁会在功能上上调各个大脑区域的 nAChR，尽管这种上调的行为后果尚不清楚。在中脑中，含有 α4 亚基的 nAChR 在 GABA 能神经元中选择性上调，但在 DA 能神经元中则不然。 R21 提案的目标是深入了解 α4 亚基的这种神经元亚型选择性功能上调如何影响尼古丁奖励行为。具体目标一是利用病毒介导的基因传递来选择性地表达小鼠 VTA GABA 能神经元中的功能获得性 α4 亚基，并与对照动物相比测量尼古丁介导的奖励行为。具体目标二将使用免疫组织化学和生物物理方法来确定尼古丁增加的 GABA 能神经元激活如何影响 VTA DA 能神经元活性。这些研究的结果不仅有助于确定 GABA 能神经元在尼古丁奖励中的作用，而且还应该揭示 nAChR 上调的行为后果。