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

• 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
• 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

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.

项目总结/摘要 虽然吸烟对健康的不利影响使其成为可预防的死亡的主要原因， 在世界范围内，目前的戒烟疗法效果甚微，这突出了对更好的戒烟方法的需求。 了解尼古丁成瘾的病理生理学基础。最近的研究发现， 未充分研究的回路，即缰核-脚间核（Hb-IPN）轴，作为尼古丁的关键回路 戒断症状特别是，在小鼠模型中尼古丁戒断期间，IPN内的神经元 表现出增加的活动，触发躯体（身体）戒断症状，以及情感 症状包括焦虑增加。尽管对神经递质的输入和 先前的工作和初步数据表明，IPN内调节神经元活动的受体信号传导 起源于中缝正中核的多巴胺能神经元支配IPN。因此，此R21的目标是 确定IPN 5-羟色胺和尼古丁能受体信号传导在尼古丁戒断行为中的作用。要求1 将检验中缝核神经元投射并调节IPN放电的假设 神经元通过血清素受体信号传导。该假设将使用光遗传学， 急性中脑切片的生物物理学、分子学和药理学方法。目标2将测试 假设在体内激活进入IPN的肾上腺素能输入将调节躯体和/或情感 尼古丁依赖小鼠模型中的尼古丁戒断症状。该假设将通过以下方式进行检验： 体内光遗传学方法与行为和脑区域特异性药物输注的组合。是 预计在尼古丁戒断期间，描述血清素在IPN中的作用将导致 确定戒烟的新型血清素受体靶点。