In vivo Characterization of PRA078C in the Rat Cocaine Reinstatement Model

药物成瘾是一种严重的、未得到满足的医疗状况，具有全球影响。根据2017年全国调查 在药物使用和健康方面，美国有超过3050万12岁以上的人报告使用非法药物。 在过去30天里，有超过750万人对非法药物上瘾。每年处理 这一问题超过6 000亿美元，对个人健康和福祉的影响很大。药物滥用是 与心血管疾病、中风、癌症、肺病以及艾滋病毒和肝炎的风险增加有关 感染可卡因是最常滥用的非法药物之一，这种药物的负面影响是 2011年药物滥用警告网络（DAWN）报告显示， 由于使用可卡因，需要医院急诊室服务。尽管有明确和令人信服的 需要，没有FDA批准的药物用于治疗可卡因成瘾。然而，众所周知， 可卡因通过中皮质边缘多巴胺（MCL-DA）系统发挥作用，也称为 奖励制度MCL-DA内的多巴胺释放和重吸收系统被急性和慢性脑缺血改变。 长期接触可卡因以前已经证明， MCL-DA活性和延伸到大脑该区域的多巴胺能神经元。此外，几项研究 已经证明，5-羟色胺（5-HT）释放多巴胺能神经元调节多巴胺能神经元的活性， 在正常条件下和可卡因的存在下，MCL-DA系统的这些区域中的神经元。 多巴胺能和多巴胺能信号之间的明显联系表明，调节5-HT信号 可能是治疗可卡因成瘾的可行方法我们已经发现了一系列新的，类似药物的5-HT 7 拮抗剂包括先导化合物PRA 073 C，其在可卡因中产生统计学显著的 复吸大鼠成瘾模型的初步研究。在这个项目中，我们将产生 可卡因成瘾大鼠恢复模型中的依赖性数据。这些数据将支持我们继续 将该化合物推进到临床前IND中，使得能够研究作为可卡因成瘾的治疗。

Drug addiction is a major, unmet medical condition with a global impact. According to the 2017 National Survey on Drug Use and Health, over 30.5 million people over the age of 12 in the U.S. had reported using an illicit drug in the past 30 days, and >7.5 million people were addicted to illicit drugs. The annual cost of dealing with this issue exceeds $600 billion, and the impact of individual health and wellness is significant. Drug abuse is linked to increased risks of cardiovascular disease, stroke, cancer, lung disease, as well as HIV and hepatitis infection. 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 over 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 addiction. It is, however, known that cocaine exerts its effects via the mesocorticolimbic dopamine (MCL-DA) system, also known as the reward system. Dopamine release and reabsorption systems within the MCL-DA are altered by both acute and chronic exposure to cocaine. 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. The apparent link between dopaminergic and serotonergic signaling suggests that modulating 5-HT signaling may be a viable approach to cocaine addiction. We have identified a series of novel, drug-like 5-HT7 antagonists that include a lead compound, PRA073C, which produces a statistically significant in cocaine reinstatement rat model of addiction in our preliminary studies. In this program, we will generate dose dependency data in the rat reinstatement model of cocaine addiction. This data will support our continued advancement of this compound into pre-clinical IND enabling studies as a treatment for cocaine addiction.