Serotonin-7 receptors and Alcohol-seeking Behaviors

5-羟色胺-7 受体和饮酒行为

基本信息

批准号：
10659697
负责人：
Sheketha Renay Hauser
金额：
$ 49.46万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659697
关键词：
Abstinence Agonist Alcohol dependence Alcoholism Alcohols Alzheimer&apos s Disease Anxiety Behavior Behavior Control Chronic Cognitive Cues Data Development Dorsal Drug Addiction Drug Controls Drug Withdrawal Symptoms Environment Exposure to Goals Human Incubated Knowledge Laboratories Measures Mediating Mental Depression Microdialysis Modeling Nature Nucleus Accumbens Pharmaceutical Preparations Play Precipitating Factors Recovery Recurrence Regulation Relapse Research Rodent Role Serotonin Site System Techniques Testing Therapeutic Time Viral Vector Western Blotting alcohol abuse therapy alcohol craving alcohol seeking behavior antagonist attenuation craving drug craving drug reward drug seeking behavior experimental study extracellular knock-down neural circuit neurochemistry overexpression painful neuropathy pharmacologic prolonged abstinence receptor receptor expression relapse prevention response serotonin 7 receptor therapeutic target

项目摘要

ABSTRACT: Drug addiction can be characterized as a chronic reoccurring illness. The relapse rate of alcoholism is particularly high (75-95%). It has been hypothesized that drug craving is a critical precipitating factor to relapse and drug craving is influenced by the amount of time abstinent, the exposure to the drug-paired environment, or drug-paired cues. Convergent data in rodents and humans have indicated that drug-paired environment or drug-paired cues' ability to elicit drug-craving intensifies with the passage of time during early abstinence, which can be referred to as ‘cue incubation of drug craving’. The serotonin (5-HT) system is thought to play a role in the development of alcohol addiction as well as play an important role in the control of drug-seeking and sensitivity to drug reward and drug cues. The 5-HT7 receptor has been researched as a potential therapeutic target for various conditions such as anxiety, depression, neuropathic pain, Alzheimer’s disease, and drug addiction. The activation of 5-HT7 receptors can regulate ‘behavior control,’ drug-withdrawal symptoms, and cognitive behaviors. However, there is a gap in knowledge of the involvement of the 5-HT7 receptor in mediating alcohol (EtOH)-seeking behaviors. Extensive preliminary data conducted in our laboratory have indicated that the systemic and site-specific, specifically in the nucleus accumbens shell (AcbSh), pharmacological manipulation of 5-HT7 receptor bidirectionally mediates context- and cue-induced EtOH-seeking. There is a critical need for therapeutic treatments for EtOH- seeking behaviors and we propose that the 5-HT7 receptors need to be further researched as potential targets for treatments of alcohol ‘craving’ behaviors. Understanding 5-HT7 mechanisms contributing to the ‘incubation’ of cue-induced EtOH-seeking is very important for developing strategies to reduce or prevent relapse. The Pavlovian Spontaneous Recovery (PSR) model of EtOH seeking, pharmacological techniques, and viral vectors will be used to examine the temporal effects of ‘incubation’ of cue-induced EtOH-seeking behaviors and determine 5-HT7 receptors' involvement in regulating these behaviors. Western blot techniques will be used to examine cellular mechanisms in ‘behavioral control’ neural circuitry and the alterations of 5-HT7 receptors expression. Microdialysis and pharmacological techniques will be used to examine the involvement of 5-HT7 receptors' effects on DA and 5-HT release within the AcbSh associated with temporal aspects of ‘incubation’ of cue-induced EtOH-seeking. Therefore, we propose to test the hypothesis that 5-HT7 receptors mediate the incubation’ of cue-induced EtOH-seeking during abstinence by regulating extracellular levels of DA and 5-HT in the AcbSh and that this response is mediated by the regulation of 5HT7 receptor expression in the AcbSh dorsal raphe circuit.

抽象的：吸毒成瘾可以被描述为一种慢性复发性疾病，酗酒的复发率是。特别高（75-95%），人们重新认识到药物渴望是一个关键的诱发因素。复发和药物渴望受到戒断时间、接触配对药物的影响环境或药物配对线索啮齿动物和人类的趋同数据表明药物配对。环境或药物配对线索引发药物渴望的能力随着时间的推移而增强早期戒断，这可以被称为“药物渴望的暗示孵化” 血清素（5-HT）系统。被认为在酒精成瘾的发展中发挥着作用，并且在酒精成瘾中发挥着重要作用 5-HT7 受体控制药物寻求以及对药物奖励和药物线索的敏感性。研究作为多种疾病的潜在治疗靶点，如焦虑、抑郁、神经病 5-HT7 受体的激活可以调节“行为”。然而，人们对药物戒断症状和认知行为的认识存在差距。 5-HT7 受体参与介导酒精 (EtOH) 寻求行为。我们实验室进行的数据表明，系统性和具体地点，特别是在伏隔核壳 (AcbSh)，5-HT7 受体的药理学操作双向介导背景和线索诱导的乙醇寻求迫切需要治疗乙醇。行为寻求，我们建议 5-HT7 受体需要进一步研究作为潜在的了解 5-HT7 机制有助于治疗酒精“渴望”行为。线索诱导的乙醇寻求的“孵化”对于制定减少或预防的策略非常重要寻找乙醇的巴甫洛夫自发恢复（PSR）模型、药理学技术、病毒载体将用于检查线索诱导的乙醇寻求“孵化”的时间效应行为并确定 5-HT7 受体参与调节这些行为。技术将用于检查“行为控制”神经回路和 5-HT7受体表达的改变将被用于微透析和药理学技术。检查 5-HT7 受体对 AcbSh 相关的 DA 和 5-HT 释放的影响因此，我们建议测试线索诱导的乙醇寻求的“孵化”。假设 5-HT7 受体介导禁欲期间提示诱导的 EtOH 寻求的“孵化” 调节 AcbSh 中 DA 和 5-HT 的细胞外水平，并且这种反应是由 AcbSh 中缝背侧回路中 5HT7 受体表达的调节。