In Vivo Characterization of 5-HT7 Modulators in Rat Models of Cocaine Use Disorder

可卡因是最常被滥用的非法药物之一，这种药物的负面影响显而易见。 在2011年药物滥用警告网络(曙光)的报告中显示，需要&gt；500,000名患者 医院急诊科因使用可卡因而服务。尽管有明确而迫切的需求， 目前还没有FDA批准的治疗可卡因使用障碍(CUD)的药物。可卡因会产生 兴奋是通过大脑中皮质边缘多巴胺(MCL-DA)系统实现的，也被称为奖赏系统。多巴胺 急性和长期接触可卡因都会改变MCL-DA内的释放和运输系统。 随着时间的推移和持续使用，可卡因将在额外的神经回路中产生适应，导致 执行功能和决策过程，并对用户造成负面情绪影响。一直以来 先前研究表明，在MCL-DA活性和5-羟色胺能神经元之间存在实质性的相互作用 延伸到大脑的这一区域。此外，一些研究表明，5-羟色胺(5-羟色胺) 释放5-羟色胺能神经元调节MCL-DA这些区域的多巴胺能神经元的活动 系统在正常情况下和在可卡因存在的情况下。DA和5-HT7信令之间的链路 提示调制5-HT7信号可能是一种可行的治疗CUD的新方法。 除了5-HT7拮抗调节MCL-DA系统的潜力外，我们在这个项目中的策略 源于大量文献表明5-HT7受体在改善注意力定势转移中的作用， 逆转学习和临床前分析中的消亡。通过提高认知灵活性和促进灭绝 除了在MCL-DA中调节奖赏外，我们还提出选择性5-HT7受体拮抗剂 是治疗CUD所需的药物治疗策略。我们已经确定了一系列新奇的药物- 如5-HT7受体拮抗剂，可减少复吸大鼠模型中可卡因的恢复 在我们的初步研究中。我们建议测试我们的第一代铅在这种可卡因中的递增剂量 恢复模型，实现全剂量-反应。一旦实现，我们将建立在我们对 我们的5-HT7拮抗剂用于识别新的、口服生物可用、血脑屏障渗透性的最佳先导化合物 用于先进的体内疗效研究。我们将测试我们化合物的有效性，以减少持续的可卡因 作为一种潜在的维持治疗反应，并确定要提高的行为活性剂量 在一组可卡因恢复模型中进行评估，包括可卡因、线索和压力诱导的恢复。 我们假设，我们的化合物将加速或增强灭绝学习，并减少 可卡因反应，无论是由非偶然注射可卡因、相关线索或压力产生的- 由育亨宾注射所致。在这些活体筛查中发现的线索将作为临床前研究进展 候选药物，以减少复发的可能性，并改善治疗结果的CUD。

Cocaine is one of the most commonly abused illicit drugs, and the negative impact of this drug is apparent in the 2011 Drug Abuse Warning Network (DAWN) report which revealed that >500,000 patients required hospital emergency department services as a result of cocaine use. Despite the clear and compelling need, there are no FDA approved medications for the treatment of cocaine use disorder (CUD). Cocaine produces euphoria via the mesocorticolimbic dopamine (MCL-DA) system, also known as the reward system. Dopamine release and transport systems within the MCL-DA are altered by both acute and chronic exposure to cocaine. Over time and continued use, cocaine will produce adaptations in additional neural circuits resulting in impaired executive function and decision-making processes and causing negative emotional affect for users. It has been previously demonstrated that there is substantial interplay between MCL-DA activity and serotonergic neurons that extend into this region of the brain. In addition, several studies have demonstrated that serotonin (5-HT) releasing serotonergic neurons regulate the activity of dopaminergic neurons in these regions of the MCL-DA system under both normal conditions and in the presence of cocaine. A link between DA and 5-HT7 signaling suggests that modulating 5-HT7 signaling may be a viable and novel approach to CUD. In addition to the potential of 5-HT7 antagonism to regulate the MCL-DA system, our strategy in this program stems from extensive literature demonstrating the role of 5-HT7 receptors in improving attentional set shifting, reversal learning, and extinction in preclinical assays. By improving cognitive flexibility and facilitating extinction learning in addition to modulating reward in the MCL-DA, we propose that selective 5-HT7 receptor antagonists are the pharmacotherapy strategy needed in the treatment of CUD. We have identified a series of novel, drug- like 5-HT7 receptor antagonists which reduced cocaine reinstatement in a well-established rat model of relapse in our preliminary studies. We propose to test escalating doses of our first-generation lead in this cocaine reinstatement model to achieve a full dose-response. Once achieved, we will build on our understanding of the SAR for our 5-HT7 antagonists to identify novel, orally bioavailable, BBB penetrant lead compounds optimized for advanced in vivo efficacy studies. We will test the effectiveness of our compounds to reduce ongoing cocaine responding as a potential maintenance therapeutic and to identify behaviorally active doses to be advanced for evaluation in a panel of cocaine reinstatement models including cocaine-, cue- and stress-induced reinstatement. We hypothesize that our compounds will accelerate or augment extinction learning and reduce reinstatement of cocaine responding whether produced by a noncontingent injection of cocaine, associated cues, or stress- induced by injection of yohimbine. Leads identified in these in vivo screens will move forward as preclinical candidates to use as medications to reduce the potential for relapse and improve treatment outcomes for CUD.