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.

项目摘要/摘要尽管吸烟的不利健康后果使其成为可预防死亡率的主要原因世界，当前的戒烟疗法最少有效地强调了对更好的需求了解尼古丁成瘾的病理生理学。最近的工作已经确定了正在研究的电路，Habenulo-terteruncular核（HB-IPN）轴，作为尼古丁的临界电路戒断症状。特别是，在鼠标模型中的尼古丁提取期间，IPN中的神经元表现出增加的活动，引发了体细胞（身体）戒断症状，以及情感症状包括增加焦虑。尽管关于神经递质输入和调节神经元活动，先前的工作和初步数据的IPN中的受体信号传导表明源自中间raphe核的血清素能神经元支配IPN。因此，此R21的目标是确定尼古丁戒断行为中IPN 5-羟色胺和血清素能受体信号的作用。目标1 将检验以下假设，即中位raphe血清素能神经元投射并调节IPN的触发神经元通过5-羟色胺受体信号传导。该假设将使用光学遗传学的组合进行检验急性中脑切片中的生物物理，分子和药理学方法。 AIM 2将测试假设血清素能输入到体内IPN将调节体内和/或情感尼古丁依赖性小鼠模型中的尼古丁戒断症状。该假设将使用体内光遗传学方法与行为和大脑区域特异性药物输注结合使用。这是预计表征尼古丁提取过程中5-羟色胺在IPN中的作用将导致鉴定新的5-羟色胺受体靶标的用于戒烟。