Serotonin-7 receptors and Alcohol-seeking Behaviors

摘要： 药物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%）。据推测，药物渴望是一个关键的诱发因素， 复吸和药物渴望受禁欲时间的长短、暴露于药物配对的影响。 环境或药物配对线索。在啮齿动物和人类中的趋同数据表明， 环境或药物配对线索引起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作用，并在 对药物寻求的控制以及对药物奖励和药物线索的敏感性。5-HT 7受体已经被 作为各种病症的潜在治疗靶点进行研究，例如焦虑、抑郁、神经病性 疼痛、阿尔茨海默病和药物成瘾。5-HT 7受体的激活可以调节行为 控制、药物戒断症状和认知行为。然而，在知识方面存在差距， 5-HT 7受体参与调节酒精（EtOH）寻求行为。广泛的初步 在我们的实验室进行的数据表明，系统性和特定地点，特别是在 5-HT 7受体双向介导的药理学操作 情境和线索诱导的乙醇寻求。迫切需要EtOH的治疗性治疗。 寻找行为，我们建议5-HT 7受体需要进一步研究，作为潜在的 酒精“渴望”行为的治疗目标。了解5-HT 7机制有助于 线索诱导的EtOH寻求的“孵化”对于制定减少或预防的策略非常重要 复发乙醇寻求的巴甫洛夫自发恢复（PSR）模型，药理学技术， 和病毒载体将被用来检查“孵育”的时间效应的线索诱导乙醇寻求 行为和决定5-HT 7受体参与调节这些行为。Western blot 技术将被用来检查细胞机制的“行为控制”神经回路和 5-HT 7受体表达的改变。微透析和药理学技术将用于 检查5-HT 7受体对AcbSh相关的DA和5-HT释放的影响 与线索诱导的EtOH寻求的“孵化”的时间方面。因此，我们建议测试 假设5-HT 7受体介导禁欲期间线索诱导的EtOH寻求的孵育， 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5 HT 7受体表达的调节。

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.