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

NMDA NR2B 亚基对可卡因的风险选择和经济需求的贡献

• 批准号: 10400341
• 负责人: Justin Ryan Yates
• 金额: $ 1.2万
• 依托单位: NORTHERN KENTUCKY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400341
• 关键词: Animal Husbandry; Attenuated; Autoradiography; Behavior; Brain; Cocaine; Data; Data Analyses; Data Collection; Decision Making; Drug Addiction; Drug Targeting; Drug abuse; Economics; Glutamate Receptor; Glutamates; Goals; Grant; Hour; Impulsivity; Individual; Internships; Ketamine; Learning; MK801; Mental disorders; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; N-methyl-D-glutamate; Neurobiology; Neurotransmitters; Pharmaceutical Preparations; Pharmacotherapy; Rattus; Research; Rewards; Risk; Risk Behaviors; Risk-Taking; Role; Self Administration; Shock; Students; Subcutaneous Injections; Substance Use Disorder; Testing; Work; channel blockers; cocaine exposure; cocaine self-administration; comorbidity; design; efficacious treatment; experimental study; foot; male; novel; novel therapeutic intervention; psychostimulant; receptor; side effect

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.

项目概要/摘要 冒险选择是冲动的一个方面，在多种精神疾病中都可以观察到，包括物质障碍 了解冒险行为和药物滥用的共同神经生物学对于使用障碍非常重要。 为有发生物质使用障碍风险的个体设计有效的药物疗法。 神经递质谷氨酸被认为与毒瘾有关，最近的研究表明 考虑到 NR2B-，N-甲基-D-天冬氨酸 (NMDA) 谷氨酸受体参与了危险选择。 选择性拮抗剂缺乏 NMDA 受体通道观察到的拟精神病副作用 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 使用风险决策任务（RDT）治疗倾向于从事危险行为的个人。 老鼠在小而安全的奖励和大而有风险的奖励（即与足部电击配对）之间做出选择，我们 最近发现，GluN2B 选择性拮抗剂 Ro 63-1908 可以降低风险选择，但仅限于雄性大鼠。 我们目前正在确定阻断含有 NR2B 的 NMDA 受体是否能有效减弱可卡因 对表现出增加风险选择的大鼠进行自我给药（拨款的具体目标 2）。 建议确定可卡因暴露是否会差异性地改变 NR2B 亚基分布（通过受体 放射自显影）在高风险和低风险大鼠中进行，并确定 Ro 63-1908 是否可以逆转可卡因诱导的 NR2B 亚基分布的改变（具体目标 3）。 Zachary 将协助数据收集和数据处理。 具体来说，他将从事与 Yates 博士 R15 资助的具体目标 2 和 3 相关的研究。 扎卡里将学习如何处理和称重老鼠，以可卡因自我给药模式测试老鼠，交付 皮下注射、记录和分析数据以及进行畜牧业，Zachary 会阅读文章。 与他将在实习期间进行的研究相关，他将定期与耶茨博士会面 和他的其他学生讨论了这项研究，以及除了药物之外的实验进展。 管理期间，扎卡里将学习根据需要对大脑进行受体放射自显影实验。 夏季期间，Zachary 将每周工作 40 小时，持续 8 周。