Abused NMDA Antagonists: Effects on Cortical Development

滥用 NMDA 拮抗剂：对皮质发育的影响

• 批准号: 6753569
• 负责人: MARY A WILSON
• 金额: $ 16万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6753569
• 关键词: NMDA receptors; apoptosis; autoradiography; brain derived neurotrophic factor; developmental neurobiology; dextromethorphan; dizocilpine; excitatory aminoacid; fos protein; glutamate receptor; immunocytochemistry; in situ hybridization; injection /infusion; ketamine; laboratory rat; messenger RNA; morphology; morphometry; neocortex; neural plasticity; neurotransmitter antagonist; protooncogene; vibrissae

This R21 application evaluates the hypothesis that the abused NMDA antagonists ketamine and dextromethorphan, by altering the function and expression of glutamate receptors, may have detrimental effects on the development of neocortex. Abuse of drugs that inhibit the NMDA receptor, such as PCP, ketamine and dextromethorphan, is increasing among adolescents. Because NMDA receptors play a critical role in the development of neo-cortical circuitry, abuse of NMDA antagonists has the potential to permanently alter the circuitry needed for normal sensory processing and cognition. NMDA antagonists may impair brain development in several ways: altering the developmentally programmed expression of neurotransmitter receptors, impairing the development of axonal and dendritic arbors, changing the precision of cortical maps, and increasing neuronal apoptosis. The proposed experiments use a well-characterized model of neocortical development that exhibits robust activity-dependent plasticity, the rodent whisker to barrel pathway. Three glutamate antagonists will be evaluated: 1) ketamine, a short-acting dissociative anesthetic that blocks the NMDAR channel, commonly used as an anesthetic in children and abused in the Club or rave scene; 2) dextromethorphan, a cough suppressant that blocks the NMDAR channel and is abused by adolescents; 3) MK-801, a longer- acting NMDAR channel blocker with documented effects on brain development. The specific aims use the rodent barrel field model to examine the effects of these NMDA antagonists on: 1) the development of somatosensory maps and the expression of glutamate receptors, 2) programmed cell death and BDNF expression in the postnatal rat brain, 3) experience-dependent cortical plasticity. The experiments will evaluate barrel field morphologic development and plasticity, expression of glutamate receptors, downstream effects on BDNF and c- fos mRNA expression and apoptosis. Based on our previous experience, the rodent barrel field model should provide a powerful, highly sensitive assessment of the potential impact of these abused drugs on neocortical development and plasticity.

该 R21 申请评估了这样的假设：滥用的 NMDA 拮抗剂氯胺酮和右美沙芬通过改变谷氨酸受体的功能和表达，可能对新皮质的发育产生有害影响。青少年滥用抑制 NMDA 受体的药物（例如五氯苯酚、氯胺酮和右美沙芬）正在增加。由于 NMDA 受体在新皮质回路的发育中发挥着关键作用，因此滥用 NMDA 拮抗剂有可能永久改变正常感觉处理和认知所需的回路。 NMDA 拮抗剂可能以多种方式损害大脑发育：改变神经递质受体的发育程序表达、损害轴突和树突乔木的发育、改变皮质图的精确度以及增加神经元凋亡。所提出的实验使用了一个充分表征的新皮质发育模型，该模型表现出强大的活动依赖性可塑性，即啮齿动物的胡须到桶状通路。将评估三种谷氨酸拮抗剂：1）氯胺酮，一种短效解离麻醉剂，可阻断 NMDAR 通道，通常用作儿童麻醉剂，并在俱乐部或狂欢现场滥用； 2) 右美沙芬，一种止咳药，可阻断 NMDAR 通道，被青少年滥用； 3) MK-801，一种长效 NMDAR 通道阻滞剂，已证实对大脑发育有影响。具体目标是使用啮齿动物桶状场模型来检查这些 NMDA 拮抗剂对以下方面的影响：1）体感图谱的发育和谷氨酸受体的表达，2）出生后大鼠大脑中的程序性细胞死亡和 BDNF 表达，3）经验依赖性皮质可塑性。实验将评估桶状区域的形态发育和可塑性、谷氨酸受体的表达、对 BDNF 和 c-fos mRNA 表达和细胞凋亡的下游影响。根据我们之前的经验，啮齿动物桶场模型应该能够对这些滥用药物对新皮质发育和可塑性的潜在影响提供强大、高度敏感的评估。