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; 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.

抽象的： 吸毒成瘾可以被描述为一种慢性重症疾病。酒精中毒率是 特别高（75-95％）。已经假设渴望药物是 复发和渴望的渴望受戒烟时间的影响，暴露于药物。 环境或药物提示。啮齿动物和人类的收敛数据表明药物对 环境或药物生产线索的引起毒品的能力随着时间的流逝而加剧 早期的禁欲，可以称为“提示渴望毒品的提示”。 5-羟色胺（5-HT）系统 人们认为在饮酒成瘾的发展中发挥作用，并在 控制吸毒和对药物奖励和药物提示的敏感性。 5-HT7受体已经 研究是针对各种疾病的潜在治疗靶标，例如焦虑，抑郁，神经性疗法 疼痛，阿尔茨海默氏病和吸毒成瘾。 5-HT7受体的激活可以调节行为 控制，“吸毒症状和认知行为”。但是，知道 5-HT7受体参与介导酒精（ETOH）寻求行为。广泛的初步 在我们的实验室中进行的数据表明，全身和特定地点的数据，特别是在 伏隔核（ACBSH），5-HT7受体双向介导的药物操纵 上下文和提示引起的寻求ETOH。对于ETOH- 寻求行为，我们建议需要进一步研究5-HT7受体 饮酒“渴望”行为的靶标。了解5-HT7机制有助于 提示引起的寻求ETOH的“孵化”对于制定减少或预防的策略非常重要 复发。寻求EtOH的Pavlovian自发回收（PSR）模型，药物技术， 病毒向量将用于检查提示引起的EtOH寻求ETOH的“孵育”的临时作用 行为并确定5-HT7受体参与确定这些行为。蛋白质印迹 技术将用于检查“行为控制”神经回路中的细胞机制和 5-HT7受体表达的改变。微透析和药物技术将用于 检查5-HT7受体对ACBSH相关的DA和5-HT释放的影响的参与 具有提示引起的寻求Etoh的“孵化”的暂时方面。因此，我们建议测试 假设5-HT7受体介导了在戒酒期间介导提示诱导的ETOH寻求的孵育 调节ACBSH中的细胞外DA和5-HT水平，并且该反应是由 ACBSH背raphe回路中5HT7受体表达的调节。