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

项目总结/摘要 冒险选择是冲动的一个方面，在几种精神疾病中观察到，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 设计有效的药物治疗，为个人的风险，发展物质使用障碍。 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）谷氨酸受体参与风险选择。考虑到NR 2B- 选择性拮抗剂没有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， 治疗有从事危险行为倾向的人。NR 2B亚单位拮抗剂艾芬地尔是 有效地阻断吗啡的奖励作用，吗啡是一种具有高滥用潜力的阿片类药物。因为 艾芬地尔对肾上腺素能受体具有高亲和力，对高选择性NR 2B亚单位的进一步研究 需要拮抗剂来确定该亚基是否是治疗疾病的潜在分子靶点 具有过度风险的特点。高选择性NR 2B拮抗剂Ro 63-1908可降低风险选择， 在大鼠中，以概率贴现法测量;然而，只有在以下情况下才能观察到这种效应： 在整个会话中获得大的奖励增加，提出了关于这个任务的有效性来衡量的问题 冒险的选择因此，本提案的第一个目标是进一步阐明NR 2B亚基在细胞内的作用。 通过在风险决策任务（RDT）中测试Ro 63-1908的作用， 其中大鼠在小的、安全的奖励和大的、有风险的奖励之间进行选择（即，与足部电击配对）。 使用RDT是理想的，因为在这项任务中的表现是预测可卡因自我管理。的 第二个目标是确定阻断含NR 2B的NMDA受体是否能有效地减弱可卡因 大鼠自我给药显示风险选择增加。该提案的第三个目标是确定 可卡因暴露差异改变NR 2B亚基分布（通过受体放射自显影），在高和低浓度 以确定Ro 63-1908是否可以逆转可卡因诱导的NR 2B亚单位的改变 分布

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. The NR2B subunit antagonist ifenprodil is effective in blocking the rewarding effects of morphine, an opiate that has high abuse potential. Because ifenprodil has high affinity for adrenergic receptors, additional research with highly selective NR2B subunit antagonists is needed to determine if this subunit is a potential molecular target for treating disorders characterized by excessive risk. The highly selective NR2B antagonist Ro 63-1908 decreases risky choice, as measured in probability discounting, in rats; however, this effect is only observed when the probability of obtaining a large reward increases across the session, raising issues about the validity of this task to measure risky choice. Thus, the first goal of this proposal is to further elucidate the role of the NR2B subunit of the NMDA receptor in risky decision making by testing the effects of Ro 63-1908 in 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). Using the RDT is ideal because performance in this task is predictive of cocaine self-administration. The second goal is to determine if blocking NR2B-containing NMDA receptors is efficacious in attenuating cocaine self-administration in rats displaying increased risky choice. The third 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.