Serotonin receptor signaling in the interpeduncular nucleus and nicotine withdrawal

脚间核中的血清素受体信号传导与尼古丁戒断

基本信息

批准号：
9387789
负责人：
ANDREW R TAPPER
金额：
$ 20.52万
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：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9387789
关键词：
5-Hydroxytryptophan Abstinence Acute Affective Affective Symptoms Agonist Aminobutyric Acids Anxiety Behavior Behavioral Biophysics Brain region Bupropion Chronic Cognitive Coupled Data Development Dose Electrophysiology (science)Exhibits FDA approved Face Functional disorder Glean Goals Health Infusion procedures Limb structure Measures Medial Mediating Mental Depression Midbrain structure Molecular Molecular Target Mus Neurons Neuropeptides Neurotransmitters Nicotine Nicotine Dependence Nicotine Withdrawal Nicotinic Receptors Optics Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacology Placebos Potassium Receptor Signaling Relapse Rodent Role Serotonin Signal Transduction Slice Smoker Smoking Somatostatin Substance Withdrawal Syndrome Sweat Sweating System Testing Therapeutic Withdrawal Withdrawal Symptom Work biophysical techniques brain circuitry gamma-Aminobutyric Acid in vivo insight interpeduncular nucleus molecular targeted therapies mortality mouse model nicotine replacement novel optogenetics patch clamp postsynaptic neurons raphe nuclei receptor expression receptor function response reward circuitry selective expression serotonin receptor small molecule smoking cessation smoking intervention varenicline

项目摘要

Project Summary/Abstract While adverse health consequences of smoking make it the primary cause of preventable mortality in the world, current therapies for smoking cessation are minimally effective highlighting the need for a better understanding of the pathophysiology underlying nicotine addiction. Recent work has identified an understudied circuit, the habenulo-interpeduncular nucleus (Hb-IPN) axis, as a critical circuit in nicotine withdrawal symptoms. In particular, during nicotine withdrawal in mouse models, neurons within the IPN exhibit increased activity triggering both somatic (physical) withdrawal symptoms, as well as affective symptoms including increased anxiety. Although little is known regarding the neurotransmitter input and receptor signaling within the IPN that modulates neuronal activity, previous work and preliminary data indicate serotonergic neurons originating in the median raphe nucleus innervate the IPN. Thus, the goal of this R21 is to identify a role for IPN serotonin and serotonergic receptor signaling in nicotine withdrawal behaviors. Aim 1 will test the hypothesis that median raphe serotonergic neurons project to, and modulate the firing of IPN neurons via serotonin receptor signaling. This hypothesis will be tested using a combination of optogenetic, biophysical, molecular, and pharmacological approaches in acute midbrain slices. Aim 2 will test the hypothesis that activation of serotonergic inputs into the IPN in vivo will modulate somatic and/or affective nicotine withdrawal symptoms in a mouse model of nicotine dependence. This hypothesis will be tested using in vivo optogenetic approaches in combination with behavior and brain region specific drug infusions. It is anticipated that characterizing the role of serotonin in the IPN during nicotine withdrawal will lead to identification of novel serotonin receptor targets for smoking cessation.

项目概要/摘要虽然吸烟对健康造成的不良后果使其成为可预防死亡的主要原因在世界范围内，目前的戒烟疗法效果甚微，这突出表明需要更好的戒烟疗法了解尼古丁成瘾的病理生理学。最近的工作已经确定了一个正在研究的回路，缰核-脚间核（Hb-IPN）轴，作为尼古丁的关键回路戒断症状。特别是，在小鼠模型的尼古丁戒断过程中，IPN 内的神经元表现出活动增加，引发躯体（身体）戒断症状以及情感症状包括焦虑加剧。尽管人们对神经递质输入和 IPN 内调节神经元活动的受体信号传导，之前的工作和初步数据表明起源于中缝核的血清素能神经元支配 IPN。因此，R21的目标是确定 IPN 血清素和血清素受体信号在尼古丁戒断行为中的作用。目标1 将检验中缝血清素能神经元投射并调节 IPN 放电的假设神经元通过血清素受体信号传导。该假设将通过光遗传学、急性中脑切片的生物物理、分子和药理学方法。目标 2 将测试假设激活体内 IPN 的血清素输入将调节躯体和/或情感尼古丁依赖小鼠模型中的尼古丁戒断症状。该假设将使用以下方法进行检验体内光遗传学方法与行为和大脑区域特定药物输注相结合。这是预计在尼古丁戒断过程中表征 IPN 中血清素的作用将导致识别新的戒烟血清素受体靶标。