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/文摘