Molecular target and circuitry underlying the preclinical effects of psychedelics in models of opioid use disorder

总结 2020年，美国发生了91，799例药物过量死亡，其中超过三分之一是 与合成阿片类药物有关阿片类药物使用障碍（OUD），与其他物质使用障碍一样 (SUD)，其特征是适应不良的行为分配远离其他有益的方面， 长期使用后的寿命以及很大的复发率。虽然药物治疗存在于 OUD，他们往往只针对阿片受体，而不是潜在的机制 在适应不良行为背后。血清素（5-羟色胺; 5-HT）参与 调节渴望和调节激励奖励相关行为，被认为是 由于外部和内部刺激的自上而下的处理方法。5-羟色胺2A受体 （5-HT 2AR）广泛分布在整个大脑中，并且最密集地分布在V层锥体 大脑皮层的神经元这些皮质锥体神经元投射到几个皮质下区域， 包括与成瘾的神经生物学有关的脑桥核。5- HT 2AR是经典致幻剂的主要目标，它会改变过程 通过激活这些受体与认知、知觉和感觉处理相关。这些 化合物可以具有改变与奖励相关行为相关的行为的能力， 例如环境诱发复发，这在药物使用障碍中起很大作用。 此外，这些化合物正在临床试验中研究其治疗物质 使用障碍。这项拟议中的研究将调查迷幻药是否能改变与药物有关的 行为和皮质5-HT 2AR在这些行为的调制中的作用。本研究将 集中在色胺迷幻药，psilocybin，它有一个化学型非常相似的血清素 主要激活5-HT 2AR和5-HT 1 R。在整个拟议的研究中，我将评估 5-HT 2AR的作用，通过利用cre重组酶病毒载体传递，这将允许我 评估5-HT 2AR的特定位点以及这些受体的激活如何调节药物环境 相关行为。这项研究的成功将确定这背后的重要机制 这项研究的成功将确定这背后的重要机制。的成功 研究将确定这类强大药物背后的重要机制，包括电路 可以用来开发安全、不上瘾和不致幻的药物疗法 治疗OUD建议将有助于我在分子技术和动物实验方面的培训。 行为模型，以及给我机会，以提高我的科学写作，批判性 思考并为我将来成为一名独立的研究科学家做好准备。

Summary In 2020, 91,799 drug overdose deaths occurred in the United States , over a third of which were related to synthetic opioids. Opioid use disorder (OUD), like other substance use disorders (SUD), is characterized maladaptive behavioral allocation away from other rewarding aspects of life following prolonged use, as well as large rates of relapse. While pharmacotherapies exist for OUD, they tend to only target the opioid receptors rather than the underlying mechanisms behind the maladaptive behaviors. Serotonin (5-hydroxytryptamine; 5-HT) is involved in modulation of cravings and regulation of motivational reward-related behaviors, thought to be due to a top-down processing method of external and internal stimuli. Serotonin 2A receptors (5-HT2AR) are widespread throughout the brain and most densely populate layer V pyramidal neurons in the cortex. These cortical pyramidal neurons project to several subcortical regions, including the nucleus accumbens, which is associated with the neurobiology of addiction. 5- HT2ARs are the main target of classic psychedelics, which produce alterations in processes related to cognition, perception and sensory processing via activation of these receptors. These compounds may possess the ability to alter behaviors associated with reward-related behaviors, such as context-induced relapse, which plays a large part in substance use disorders. Moreover, these compounds are being studied in clinical trials for their ability to treat substance use disorders. The proposed study will investigate whether a psychedelic can alter drug-related behaviors and the role of cortical 5-HT2AR in modulation of these behaviors. This study will focus on tryptamine psychedelic, psilocybin, which has a chemotype very similar to serotonin that activates mainly 5-HT2AR and 5-HT1Rs. Throughout the proposed study, I will be assessing the role of the 5-HT2AR by utilizing cre-recombinase viral vector delivery which will allow me to assess specific loci of 5-HT2AR and how activation of these receptors modulates drug-context related behaviors. The success of this studies will identify important mechanisms behind this The success of this studies will identify important mechanisms behind this. The success of this studies will identify important mechanisms behind this powerful drug class, including circuitry that could be utilized to develop safe, non-addictive and non-hallucinogenic pharmacotherapies to treat OUD. The proposed will facilitate my training in molecular techniques and animal behavioral models as well as give me opportunities to advance my scientific writing, critical thinking and prepare me for a future as an independent research scientist.