Contribution of NMDA NR2B subunit to risky choice and economic demand for cocaine

项目摘要/摘要 风险选择是冲动的一个方面，在几种精神障碍中都能观察到，包括物质 使用障碍。了解冒险行为和药物滥用的共同神经生物学对于 为有发展成物质使用障碍风险的个人设计有效的药物疗法。 神经递质谷氨酸被认为与药物成瘾有关，最近的研究表明 N-甲基-D-天冬氨酸(NMDA)谷氨酸受体参与了风险选择。考虑到NR2B- 选择性拮抗剂缺乏NMDA受体通道观察到的拟精神分裂症副作用 阻滞剂(如MK-801和氯胺酮)，这些药物可能提供一种新的治疗方法 治疗倾向于从事危险行为的个人。使用风险决策任务(RDT)，在 在小的、安全的奖励和大的、有风险的奖励(即，伴随着脚电击)之间做出选择的老鼠，我们 最近发现，GluN2B选择性拮抗剂Ro 63-1908减少了风险选择，但仅限于雄性大鼠。 我们目前正在确定阻断含有NR2B的NMDA受体是否能有效地减轻可卡因 风险选择增加的大鼠的自我给药(GRANT的特定目标2)。另一个目标是 建议确定可卡因暴露是否通过受体不同地改变NR2B亚基分布 放射自显影)，并确定Ro 63-1908是否能逆转可卡因诱导的 NR2B亚基分布的变化(具体目标3)。扎克里将协助收集数据和数据 分析。具体地说，他将致力于与耶茨博士R15拨款的具体目标2和3相关的研究。简单地说， Zachary将学习处理和称重老鼠，在可卡因自我给药范例中测试老鼠，交付 皮下注射，记录和分析数据，并进行畜牧业。扎卡里将阅读文章 与他将在实习期间进行的研究有关，他将定期与耶茨博士会面 和他的其他学生讨论这项研究，以及实验的进展。除了药物本身 Zachary将学习为受体放射自显影实验切开大脑。根据要求， Zachary将在夏季每周工作40个小时，连续工作8周。

Project Summary/Abstract Risky choice is one facet of impulsivity that is observed in several psychiatric disorders, including substance use disorders. Understanding the shared neurobiology of risk-taking behavior and drug abuse is important for designing effective pharmacotherapies for individuals that are at risk for developing substance use disorders. The neurotransmitter glutamate is considered to be involved in drug addiction, and recent research has shown that the N-methyl-D-aspartate (NMDA) glutamate receptor is involved in risky choice. Considering NR2B- selective antagonists lack the psychotomimetic side effects observed with NMDA receptor channel blockers (such as MK-801 and ketamine), these drugs may provide a novel therapeutic approach to treating individuals predisposed to engaging in risky behaviors. Using the risky decision task (RDT), in which rats choose between a small, safe reward and a large, risky reward (i.e., paired with foot shock), we recently found that the GluN2B-selective antagonist Ro 63-1908 decreases risky choice, but only in male rats. We are currently determining if blocking NR2B-containing NMDA receptors is efficacious in attenuating cocaine self-administration in rats displaying increased risky choice (Specific Aim 2 of grant). Another goal of the proposal is to determine if cocaine exposure differentially alters NR2B subunit distribution (via receptor autoradiography) in high and low risk-taking rats and to determine if Ro 63-1908 can reverse cocaine-induced alterations in NR2B subunit distribution (Specific Aim 3). Zachary will assist with data collection and data analysis. Specifically, he will work on research related to Specific Aims 2 and 3 of Dr. Yates’ R15 grant. Briefly, Zachary will learn to handle and weigh rats, test rats in a cocaine self-administration paradigm, deliver subcutaneous injections, record and analyze data, and perform animal husbandry. Zachary will read articles related to the research he will be conducting during the internship, and he will meet regularly with Dr. Yates and his other students to discuss this research, as well as progress in the experiment. In addition to drug self- administration, Zachary will learn to section brains for receptor autoradiography experiments. As required, Zachary will work 40 hours each week for 8 weeks during the summer.