5-HT7 receptor modulation of cocaine effects

摘要 对于可卡因使用障碍(Cuds)，目前还没有被广泛接受的药物治疗方法。 在过去的十年里，可卡因的使用和过量使用有所增加。可卡因的精神作用 主要是由于单胺类神经递质的增强和延长的作用，包括5-羟色胺(5- HT)。在5-羟色胺激活的受体中，5-羟色胺7受体(5-HT7R)在多个神经中发挥作用 参与CUDS的过程，包括学习和记忆、神经可塑性、睡眠、冲动和 寻求刺激。这些受体还调节临床前模型和5-HT7R的酒精摄入量 基因多态与酒精使用障碍有关。因此，令人惊讶的是，5-HT7Rs在 与CUDS相关的行为尚未被探索。我们在雄性大鼠身上的初步数据表明，5-HT7R 激动剂和拮抗剂药物调节可卡因的自我给药，拮抗剂减少可卡因- 寻求行为。我们假设5-HT7R拮抗剂抑制可卡因，而5-HT7R激动剂增强可卡因 对可卡因的强化和激励。我们将在雄性和雌性大鼠身上测试这一假设， 每天接触可卡因以确定成瘾表型。然后我们将测试5-HT7R拮抗剂的效果， MC-RG19和可卡因激动剂AS-19，采用会话内剂量减少的方法自我给药 大鼠获得9种不同剂量的可卡因，每次10分钟，按降序排列的程序 集中精神。根据结果生成的需求曲线的行为经济学分析将用于 估计需求强度和需求弹性，它们被认为是反映强化和激励的 可卡因的特性。我们还将检查5-HT7R药物对可卡因诱导的影响 基因表达的变化，用免疫组织化学Fos蛋白作为这些变化的标志。我们 预期拮抗者会降低需求强度，增加需求弹性，而激动者会降低需求强度，增加需求弹性 会产生相反的效果模式。可卡因诱导的Fos表达的类似变化模式是 预计在与CUDS相关的中皮质边缘脑区。该项目将是第一个 描述5-HT7Rs在可卡因自我给药中的作用。如果我们的预测成立，结果将会是 提示5-HT7R拮抗剂可作为治疗CUDS的新型药物。中的区域特定变化 Fos的表达将有助于阐明5-HT7R药物对心脏的影响的神经解剖学机制 可卡因自我管理。

Summary There is still no widely accepted pharmacological therapy available for cocaine use disorders (CUDs) while over the past decade there has been a rise in cocaine use and overdoses. The psychoactive effects of cocaine are primarily due to enhanced and prolonged actions of monoamine neurotransmitters, including serotonin (5- HT). Among the receptors activated by 5HT, the 5-HT7 receptor (5-HT7R) plays a role in several neural processes involved in CUDs, including learning and memory, neural plasticity, sleep, impulsivity, and sensation-seeking. These receptors also modulate alcohol intake in preclinical models and 5-HT7R polymorphisms have been linked to alcohol use disorders. It is therefore surprising that the role of 5-HT7Rs in CUDs-related behaviors has not yet been explored. Our preliminary data in male rats suggests that 5-HT7R agonist and antagonist drugs modulate cocaine self-administration and that the antagonist decreases cocaine- seeking behavior. We hypothesize that 5-HT7R antagonists inhibit, whereas 5-HT7R agonists enhance, cocaine reinforcement and motivation for cocaine. We will test this hypothesis in male and female rats given extended access to cocaine daily to establish an addiction phenotype. We will then test effects of a 5-HT7R antagonist, MC-RG19, and an agonist, AS-19, on cocaine self-administration using a within-session, dose-reduction procedure whereby rats have access to 9 different doses of cocaine for 10 min each in descending order of concentration. A behavioral economics analysis of demand curves generated from the results will be used to estimate demand intensity and demand elasticity, which are thought to reflect the reinforcing and motivational properties of cocaine, respectively. We will also examine effects of the 5-HT7R drugs on cocaine-induced changes in gene expression, using immunohistochemistry of Fos protein as a marker of these changes. We expect that the antagonist will decrease demand intensity and increase demand elasticity, whereas the agonist will produce the opposite pattern of effects. A similar pattern of changes in cocaine-induced Fos expression is expected in mesocorticolimbic brain regions that are involved in CUDs. This project will be the first to characterize the role of 5-HT7Rs in cocaine self-administration. If our predictions are upheld, the results will suggest that 5-HT7R antagonists may be useful as novel medications for CUDs. Region-specific changes in Fos expression will shed light on the neuroanatomical mechanisms involved in the 5-HT7R drug effects on cocaine self-administration.