Serotonin-7 receptors and Alcohol-seeking Behaviors

5-羟色胺-7 受体和饮酒行为

• 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
• 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' 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

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.

摘要： 毒瘾可以被描述为一种慢性反复发作的疾病。酒精中毒的复发率是 特别高(75%-95%)。据推测，对毒品的渴望是一个关键的诱发因素 复发和对毒品的渴求受戒毒时间长短、与毒品配对接触的影响 环境，或毒品配对的线索。在啮齿动物和人类中的趋同数据表明，药物配对 环境或药物配对线索引发药物渴求的能力随着时间的推移而增强 早期戒毒，可称为“线索孕育的药物渴求”。5-羟色胺(5-HT)系统 被认为在酒精成瘾的发展过程中起着重要作用，并在 控制毒品寻觅和对毒品奖励和毒品线索的敏感性。5-HT7受体已经被 被研究为治疗各种疾病的潜在靶点，如焦虑、抑郁、神经病 疼痛、阿尔茨海默氏症和毒瘾。5-HT7受体的激活可以调节人的行为 控制、戒毒症状和认知行为。然而，对这一问题的认识存在差距。 5-HT7受体参与调节酒精(Etoh)寻求行为。广泛的初步 我们实验室进行的数据表明，系统性和特定地点的，特别是在 伏隔核壳蛋白(AcbSh)对5-HT7受体的双向调节作用 语境和线索诱导的乙醇寻找。Etoh的治疗非常需要-- 寻找行为，我们认为5-HT7受体作为潜在的可能需要进一步研究 酒精“渴求”行为的治疗目标。了解5-HT7机制 线索诱导的乙醇寻找的‘孵化’对于制定减少或预防的策略非常重要 旧病复发。寻找乙醇的巴甫洛夫自发恢复(PSR)模型，药理学技术， 病毒载体将被用来检测线索诱导的乙醇寻找的时间效应 并确定5-HT7受体参与调节这些行为。蛋白质印迹 技术将被用来检查‘行为控制’神经回路中的细胞机制，以及 5-HT7受体表达的变化。将使用微透析和药理学技术来 探讨5-HT7受体对AcbSh相关脑区DA和5-HT释放的影响 与线索诱导的乙醇寻找的“孵化”有关的时间方面。因此，我们建议测试 5-HT7受体介导线索诱导的酒精戒断潜伏期假说 调节AcbSh细胞外多巴胺和5-羟色胺的水平，这种反应是由 AcbSh背侧中缝环路5HT7受体表达的调节