5-HT7 receptor modulation of cocaine effects

总结 可卡因使用障碍（CUD）仍然没有广泛接受的药物治疗， 在过去十年中，可卡因的使用和过量使用有所增加。可卡因对精神的影响 主要是由于单胺神经递质，包括血清素（5- HT）。在5-HT激活的受体中，5-HT 7受体（5-HT 7 R）在多种神经细胞中起作用。 CUD涉及的过程，包括学习和记忆，神经可塑性，睡眠，冲动， 追求轰动效应这些受体还调节临床前模型中的酒精摄入量和5-HT 7 R 多态性与酒精使用障碍有关。因此，令人惊讶的是，5-HT 7 Rs在 与CUDS相关的行为尚未被探索。我们在雄性大鼠中的初步数据表明，5-HT 7 R 激动剂和拮抗剂药物调节可卡因自我给药，拮抗剂减少可卡因- 寻求行为。我们假设5-HT 7 R拮抗剂抑制可卡因，而5-HT 7 R激动剂增强可卡因 可卡因的强化和动机我们将在雄性和雌性大鼠中测试这一假设， 每天接触可卡因以建立成瘾表型。然后我们将测试5-HT 7 R拮抗剂的作用， MC-RG 19和激动剂AS-19对使用会话内剂量降低的可卡因自我给药的影响 大鼠按递减顺序接触9种不同剂量的可卡因，每次10分钟。 浓度.从结果中产生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，这被认为是反映加强和激励 可卡因的特性。我们还将研究5-HT 7 R药物对可卡因诱导的 基因表达的变化，使用Fos蛋白的免疫组织化学作为这些变化的标志物。我们 预期拮抗剂将降低需求强度并增加需求弹性，而激动剂 会产生相反的效果可卡因诱导的Fos表达的变化模式相似， 预期在中皮质边缘脑区域参与CUD。该项目将是第一个 表征5-HT 7 R在可卡因自我给药中的作用。如果我们的预测得到证实， 提示5-HT 7 R拮抗剂可用作治疗CUD的新药物。具体区域的变化 Fos的表达将有助于阐明5-HT 7 R药物作用于神经系统的神经解剖学机制。 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.